A patient-like swine model of gastrointestinal fibrotic strictures for advancing therapeutics.

Gastrointestinal (GI) strictures are difficult to treat in a variety of disease processes. Currently, there are no Food and Drug Administration (FDA) approved drugs for fibrosis in the GI tract. One of the limitations to developing anti-fibrotic drugs has been the lack of a reproducible, relatively inexpensive, large animal model of fibrosis-driven luminal stricture. This study aimed to evaluate the feasibility of creating a model of luminal GI tract strictures. Argon plasma coagulation (APC) was applied circumferentially in porcine esophagi in vivo. Follow-up endoscopy (EGD) was performed at day 14 after the APC procedure. We noted high grade, benign esophageal strictures (n = 8). All 8 strictures resembled luminal GI fibrotic strictures in humans. These strictures were characterized, and then successfully dilated. A repeat EGD was performed at day 28 after the APC procedure and found evidence of recurrent, high grade, fibrotic, strictures at all 8 locations in all pigs. Pigs were sacrificed and gross and histologic analyses performed. Histologic examination showed extensive fibrosis, with significant collagen deposition in the lamina propria and submucosa, as well as extensive inflammatory infiltrates within the strictures. In conclusion, we report a porcine model of luminal GI fibrotic stricture that has the potential to assist with developing novel anti-fibrotic therapies as well as endoscopic techniques to address recurring fibrotic strictures in humans.

Cryoballoon ablation for gastric pouch and/or outlet reduction in patients with weight regain post Roux-en-Y gastric bypass.

BACKGROUND: Cryoballoon ablation could induce stricture formation to achieve outlet and pouch reduction in patients regaining weight after Roux-en-Y gastric bypass (RYGB). This pilot study aimed to assess technical feasibility and short-term efficacy. METHODS: A retrospective chart review (January - November 2018) at two academic centers identified patients with weight regain post-RYGB, treated with cryoablation if pouch > 4 cm and/or outlet > 15 mm. Patients were scheduled for surveillance endoscopies at 8 weeks. RESULTS: 22 patients presented 10.5 years (SD 4.42) post-RYGB with weight regain of 30.9 kg (SD 13.7). Technical success was 89.5 % for outlet ablation and 93.0 % for pouch ablation. From baseline to 8 weeks, the outlet was reduced from 24.1 mm (95 % confidence interval [CI] 19.8 to 28.5) to 17.1 mm (95 %CI 13.1 to 21.1; P < 0.001), and pouch from 5 cm (95 %CI 4.1 to 5.9) to 3.9 cm (95 %CI 2.6 to 5.1; P < 0.05). Total body weight loss at 8 weeks was 8.1 % (SD 12.8 %). CONCLUSION: Cryoablation appears technically feasible and effective for outlet and/or pouch reduction in the short term.

Post aortic dissection: Gap between activity recommendation and real life patients aerobic capacities.

BACK GROUND: Regular exercise at a safe level, i.e. 3-5 metabolic equivalents, is recommended to improve blood pressure control and quality of life even after aortic dissection, although aerobic exercise capacities in these patients are unexplored yet. METHODS: We prospectively collected data from 105 patients with a history of post aortic dissection referred for a cardiopulmonary exercise testing (CPX) aiming to guide exercise rehabilitation. RESULTS: The population was composed of 76% of male, with a mean age of 57.9±12.4years. There were an equal distribution between the two type of dissection (47% of type A and 53% of type B aortic dissection). No cardiac event occurred during or after CPX. One third of patients have normal aerobic exercise capacity defined as peak oxygen uptake upper than 85% of their predicted capacity. Mean oxygen uptake peak was quite low 19.2±5.2ml/kg/min (5.5±1.5 metabolic equivalents). Aerobic capacity was limited by cardiac chronotropic incompetence in 42% or peripheral deconditioning in 45%. Blood pressure remained in an acceptable range during the exercise. Systolic and diastolic blood pressures were respectively 151±20 and 77±13mmHg at first ventilatory threshold. CONCLUSIONS: CPX is a safe exploration in patients with post aortic dissection syndrome. Given the fact that most of these patients are faced with significant alteration of aerobic capacities, the recommended daily practice of moderate exercise at 3-5 METS should be adapted and personalized to each patient thanks to CPX.

Macrophage migration inhibitory factor induces contractile and mitochondria dysfunction by altering cytoskeleton network in the human heart.

OBJECTIVES: Macrophage migration inhibitory factor (MIF) has been recognized as a potent proinflammatory mediator that may induce myocardial dysfunction. Mechanisms by which MIF affects cardiac function are not completely elucidated; yet, some macrophage migration inhibitory effects have been related to changes in cytoskeleton architecture. We hypothesized that MIF-induced myocardial dysfunction and mitochondrial respiration deficit could be related to cardiac cell microtubule dynamics alterations. DESIGN: Prospective, randomized study. SETTING: Experimental Cardiovascular Laboratory, University Hospital. SUBJECTS: Human myocardial (atrial) trabeculae. INTERVENTIONS: Atrial trabeculae were obtained at the time of cardiac surgery. Isometrically contracting isolated human right atrial trabeculae were exposed to MIF (100 ng/mL) for 60 minutes, in the presence or not of pretreatment with colchicine (10 µM), a microtubule-depolymerizing agent, or paclitaxel (10 µM) a microtubule-stabilizing agent. MEASUREMENTS AND MAIN RESULTS: Maximal active isometric tension curve and developed isometric force were studied. Trabeculae were then permeabilized for mitochondrial respiration studies using high-resolution oxygraphy. Heart fiber electron microscopy and visualization of ßIV tubulin and polymerized actin by confocal microscopy were used to evaluate sarcomere and microtubule disarray. Compared with controls, MIF elicited cardiac contractile and mitochondrial dysfunction, which were largely prevented by pretreatment with colchicine, but not by paclitaxel. Pretreatment with colchicine prevented MIF-induced microtubule network disorganization, excessive tubulin polymerization, and mitochondrial fragmentation. Compound-C, an inhibitor of AMP-activated protein kinase (AMPK), partially prevented contractile dysfunction, suggesting that cardiac deleterious effects of MIF were related to AMPK activation. CONCLUSIONS: MIF depresses human myocardial contractile function and impairs mitochondrial respiration. Changes in microtubule network likely promote MIF-induced cardiac dysfunction by 1) altering with mitochondrial tubular assembly and outer membrane permeability for adenine nucleotides leading to energy deficit, 2) excessive tubulin polymerization that may impede cardiomyocyte viscosity and motion, and 3) interfering with AMPK pathway.

Doxorubicin induces mitochondrial permeability transition and contractile dysfunction in the human myocardium.

In human atrial trabeculae, we examined the effects of doxorubicin on the isometric force of contraction, mitochondrial respiration, membrane potential and calcium retention capacity. Compared with untreated controls, doxorubicin induced contractile dysfunction and depression of mitochondrial respiration. Mitochondria isolated from doxorubicin-treated human atrial trabeculae displayed reduced transmembrane potential and calcium retention capacity. Cyclosporine A, a mitochondrial membrane transition pore opening blocker, prevented mitochondrial dysfunction and impaired contractile performance induced by doxorubicin. The study suggests that a mitochondrial membrane transition pore opening is involved in the development of doxorubicin cardiotoxicity in human hearts.

Late bioprosthetic mitral valve thrombosis: a link with postoperative heparin-induced thrombocytopenia?

Bioprosthetic valve thrombosis is considered extremely unlikely, thus usually allowing patients to avoid long-term anticoagulation. The authors report the case of a patient with late bioprosthetic mitral valve thrombosis associated with a history of postoperative heparin-induced thrombocytopenia. The patient successfully underwent mitral valve replacement.

Second generation of minimal invasive extracorporeal circuit: pilot study resting heart system.

Cardiopulmonary bypass (CPB) has evolved from a complex multifunctional system to the minimally invasive extracorporeal circuit (MIEC). Concerns currently exist regarding the technically demanding nature of off-pump coronary artery bypass (OPCAB) procedures, the quality of anastomosis associated with it, and the difficulty in achieving "complete revascularization." Recognizing these issues, the so-called mini-CPB concept has evolved in an effort to offer the perceived benefits of OPCAB with the technical advantages of CPB and at the same time minimize the adverse effects of full-scale CPB. The first generation of MIEC had an inherited risk of gas embolisms. Therefore, there was the introduction of the resting heart system (RHS), the main characteristic of which is the venous air removal device. The aim of this study was to describe our early experience, feasibility, and safety with this system to help others who are considering introducing this technique into their clinical practice. Using this system, we operated on 30 consecutive patients. Moderate hypothermia (33 degrees C) CPB and cold intermittent antegrade cardioplegia was used. No technical incidents were encountered. One death from multiorgan failure occurred in a patient operated on for a thoraco-abdominal aneurysm. Our own short-term experience with the RHS has been very favorable, and we will continue to explore this development in CPB technology.