Pioglitazone-incorporated microspheres targeting macrophage polarization alleviates cardiac dysfunction after myocardial infarction.

OBJECTIVES: Excessive and chronic inflammation after a myocardial infarction (MI) is associated with left ventricular remodelling and impaired cardiac function. Among inflammatory cells, macrophages play a critical role in polarizing proinflammatory M1 or the reparative M2 subtype. Pioglitazone (PGZ) is reported to regulate macrophage polarization to the M2 subtype. Our goal was to validate the therapeutic effects and the mechanisms of PGZ utilizing a drug delivery system. METHODS: Poly L-lactic-co-glycolic acid microspheres (MS) incorporating PGZ were prepared. To validate the therapeutic potential of PGZ-MS, Sprague-Dawley rats were subjected to permanent left coronary artery ligation to induce an MI. Placebo-MS (100 µg) or PGZ-MS (100 µg) was injected to the infarct region just after induction. Cardiac function and size were assessed by echocardiography. At 28 days after surgery, the rats were sacrificed, and the excised hearts were evaluated histologically. RESULTS: Sustained release of PGZ from the PGZ-MS was confirmed in vitro. PGZ-MS significantly rehabilitated cardiac dysfunction after an MI (fractional shortening: MI vs MI+placebo-MS vs MI+PGZ-MS, 24.4 ± 1.1 vs 24.3 ± 1.6 vs 32.2 ± 1.4%; P = 0.0035) with reverse remodelling. Immunohistochemical analyses revealed that PGZ-MS enhanced macrophage polarization (ratio of M2 subtype: 0.39 ± 0.03 vs 0.42 ± 0.02 vs 0.54 ± 0.02; P = 0.0004) and attenuated apoptosis of cardiomyocytes in the ischaemic border zone. CONCLUSIONS: We confirmed macrophage polarization by sustained release of PGZ, which resulted in amelioration of adverse left ventricular remodelling and cardiac dysfunction. Drug delivery system-based macrophage polarization might serve as a promising strategy in cardiac regenerative therapy for ischaemic heart disease. (241 words).

[One-stage Radical Surgery for Aortoesophageal Fistula after Graft Replacement of Descending Aorta].

A 31-year-old woman was referred to our institution because of aortoesophageal fistula (AEF) six months after the descending aortic replacement for acute aortic dissection. We operated one-stage repair of the AEF. Thoracoscopic esophagectomy was firstly performed in prone position from right thoracic cavity, and then the esophagus was reconstructed with gastric conduit via posterior mediastinal route with omental flap. Secondly, graft replacement of the descending aorta using lateral oblique straight incision was performed and the graft was covered with omental flap simultaneously. The postoperative course was uneventful, and she started oral intake on the 13th day after surgery. Although the one-stage surgery for the AEF is highly invasive, it could be a good option for selected cases.

Management of retrosternal adhesion after median sternotomy by controlling degradation speed of a dextran and ε-poly (L-lysine)-based biocompatible glue.

OBJECTIVE: Retrosternal adhesion after median sternotomy possibly raises the risk of cardiac injury at resternotomy. A biodegradable glue "Lydex" is composed of food additives, dextran and ε-poly (L-lysine), and the degradation speed can be controlled by the composition. In the present study, we evaluated the preventative effect of Lydex on retrosternal adhesion and the relationship between degradation speed and the progression of retrosternal fibrosis. METHODS: Japanese white rabbits are subjected to median sternotomy. Lydex 1, 2 and 3 were loaded at the retrosternal space of rabbits in allocated groups before sternal closure, respectively (n = 11 for each group). Retrosternal adhesion was macroscopically evaluated after surgery. Retainment of Lydex, retrosternal fibrosis and the infiltration of macrophages are histologically evaluated, respectively. RESULTS: All Lydex groups exhibited less retrosternal adhesion at 4 weeks after loading compared to unloaded control. The degradation speed of Lydex varied according to the compositions. Lydex with faster degradation (Lydex 2 or Lydex 3) showed lower progression of retrosternal fibrosis compared to that with slower degradation (Lydex 1) [fibrosis ratio: control vs Lydex 1 vs Lydex 2 vs Lydex 3: 0.60 ± 0.15 vs 0.18 ± 0.17 vs 0.00 ± 0.00 vs 0.00 ± 0.00, P = 0.0005 (Lydex 1 vs Lydex 2), P = 0.0005 (Lydex 1 vs Lydex 3)]. Retrosternal infiltrations of macrophages in Lydex 1 and Lydex 3 groups are not higher compared to that in unloaded control. CONCLUSIONS: The degradation speed of Lydex could be controlled according to the compositions. The degradation speed affected the progression of retrosternal fibrosis.

[Emergent Re-do Mitral Valve Replacement for Prosthetic Valve Endocarditis with Increasing Obstruction of Mitral Valve].

We report a surgical case of active infective prosthetic biologic mitral valve endocarditis with hemodynamic deterioration with increasing obstruction of mitral valve. The patient developed rapid hemodynamic deterioration, therefore, we performed emergent re-do mitral valve replacement using SJM prosthetic valve in the setting of supra-annular position. The postoperative course was uneventful.

Safety and efficacy of sustained release of basic fibroblast growth factor using gelatin hydrogel in patients with critical limb ischemia.

As a form of therapeutic angiogenesis, we sought to investigate the safety and efficacy of a sustained-release system of basic fibroblast growth factor (bFGF) using biodegradable gelatin hydrogel in patients with critical limb ischemia (CLI). We conducted a phase I-IIa study that analyzed 10 CLI patients following a 200-µg intramuscular injection of bFGF-incorporated gelatin hydrogel microspheres into the ischemic limb. Primary endpoints were safety and transcutaneous oxygen pressure (TcO2) at 4 and 24 weeks after treatment. During the follow-up, there was no death or serious procedure-related adverse event. After 24 weeks, TcO2 (28.4 ± 8.4 vs. 46.2 ± 13.0 mmHg for pretreatment vs after 24 weeks, p < 0.01) showed significant improvement. Regarding secondary endpoints, the distance walked in 6 min (255 ± 105 vs. 318 ± 127 m, p = 0.02), the Rutherford classification (4.4 ± 0.5 vs. 3.1 ± 1.4, p = 0.02), the rest pain scale (1.7 ± 1.0 vs. 1.2 ± 1.3, p = 0.03), and the cyanotic scale (2.0 ± 1.1 vs. 0.9 ± 0.9, p < 0.01) also showed improvement. The blood levels of bFGF were within the normal range in all patients. A subanalysis of patients with arteriosclerosis obliterans (n = 7) or thromboangiitis obliterans (Buerger's disease) (n = 3) revealed that TcO2 had significantly improved in both subgroups. TcO2 did not differ between patients with or without chronic kidney disease. The sustained release of bFGF from biodegradable gelatin hydrogel may offer a safe and effective form of angiogenesis for patients with CLI.

[Surgical treatment for infective prosthetic mitral valve endocarditis with cardiogenic shock; report of a case].

We report a surgical case of active infective prosthetic mitral valve endocarditis with cardiogenic shock. The causative organism was methicillin-resistant coagulase negative Staphylococci (MRCNS) During medical treatment, the prosthetic valve was abruptly detouched partially from the mitral annulus, and the patient developed rapid hemodynamic deterioration. We performed emergency re-do mitral valve replacement. The postoperative course was uneventful. Rapid establishment of femoro-femoral bypass was very effective for the emergency re-do valve surgery.

[Total arch replacement for ruptured Stanford type B aortic dissection with thrombosed pseudolumen presenting hemodynamic deterioration].

We report 2 cases of ruptured type B aortic dissection with thrombosed pseudolumen presenting hemodynamic deterioration which is a life-threatening condition. In such cases, surgical treatment often resulted in high mortality rates. We underwent total arch replacement via median sternotomy. In both cases, postoperative courses were uneventful. This approach ensured us wider operative field to establish cardiopulmonary bypass quickly, and to perform distal anastomosis without much difficulty.

[Valve replacement for tricuspid infective endocarditis presenting paradoxical cerebral embolism].

Tricuspid valve infective endocarditis( IE) accounts for 5 to 10% of all IE. We encountered a 50-year old man who suffered from tricuspid valve IE presenting paradoxical multiple cerebral embolism with intracranial hemorrhage. On 6th day from his admission, we performed valve replacement for intractable tricuspid infective endocarditis regardless of acute phase of intracranial hemorrhage. The patient had an uneventful postoperative course with no neurological symptoms.

[Surgical ventricular restoration for functional mitral regurgitation].

BACKGROUND: This study evaluated the effectiveness and limitations of the surgical ventricular restoration(SVR)procedure in patients with functional mitral regurgitation(FMR)due to severe leaflet tethering. METHODS: From 2008 to 2012, FMR was treated in 39 patients by either mitral annuloplasty(MAP)alone( group M:n=17) or MAP combined with SVR( group S:n=22). Preoperatively, patients in group S had lower ejection fraction( EF), larger left ventricle, and more severe mitral regurgiation( MR) comparing to group M. RESULTS: The SVR performed in group S included posterior wall exclusion(Batista)in 10, septal-anteriorventricular exclusion in 8, overlapping ventriculoplasty in 2, and others in addition to papillary muscle approximation(PMA). Coronary revascularization was more common in the group M. Hospital mortality were 18% in group S and 0 in group M. There were no significant improvement on EF in both group, but left ventricular( LV) dimensions decreased significantly in both groups. Also, MR grade decreased significantly in both groups. Leaflet tethering was improved significantly in group S. There were 5 and 1 late deaths in group S and M, respectively. CONCLUSION: SVR in addition to MAP yielded excellent reduction of leaflet tethering and MR in patients with severe LV dilatation. However, long-term outcomes were poor in those requiring SVR.

A novel detachable filter to prevent thromboembolism during endovascular surgery.

OBJECTIVE: Thromboembolism remains a serious complication during endovascular surgery. Commercially available filter devices, which are unified with the stenting systems, provide short-time performance owing to the adhesion of thrombus to the filters themselves. We have, therefore, developed a new detachable filter that can be used in all major aortic branches and shows greater longevity. The present study assessed the efficacy of the new detachable filter and examined the feasibility of deploying and retrieving the filters. METHODS: We first performed in vitro studies. Our experimental flow model used silicon tubing to simulate the aortic branches. Polystyrene-divinylbenzene microspheres (100 and 200 µm in diameter), which simulated embolic particles, were injected into the tubing after the detachable filter was deployed. The capture efficacy (number of microspheres trapped in the detachable filter/total injected microspheres) was calculated. In the in vivo studies, the detachable filters were implanted into the carotid, visceral, and renal arteries of 5 mongrel dogs. Angiography was performed every 30 minutes. At 5 hours after implantation, each detachable filter was retrieved by a gooseneck snare catheter. RESULTS: In the in vitro studies, our detachable filters showed high capture efficacy, capturing 99.2% of the 100-µm microspheres and 99.4% of the 200-µm microspheres. In the in vivo studies, all detachable filters were successfully deployed into the major branches. Each angiographic study revealed smooth flow without any embolic obstruction of the filter. At 5 hours after deployment, all devices were completely retrieved by the snare catheter without aortic injury. CONCLUSIONS: The new detachable filter showed high efficacy in capturing the particles. All detachable filters were successfully deployed for 5 hours, and the filters were retrieved from the aortic branches without any complications. This novel detachable filter can help prevent serious distal thromboembolism during endovascular surgery.

[Surgical treatment for ischemic mitral regurgitation].

BACKGROUND: Ischemic mitral regurgitation (IMR) is characterized by annular dilation and restricted leaflet closure with increased leaflet tethering caused by displaced attachment of the papillary muscles. Our surgical strategy for IMR consists of mitral annuloplasty (MAP) and additional left ventricular restoration procedures as needed. When the left ventricular dilation and mitral tethering are mild, we perform MAP alone. On the other hand, we add papillary muscle approximation (PMA) through left ventriculotomy with or without infero-posteiror wall exclusion (the Batista procedure) when left ventricular dilatation and leaflet tethering are severe. METHODS: From November 2007 to April 2011, we surgically treated 19 patients with IMR at our institution. Of those, 13 patients underwent MAP alone (group M) and 6 patients underwent MAP and PMA (group P). RESULTS: There were no hospital deaths. Postoperatively, echocardiography showed no or mild mitral regurgitation (MR) in all patients except 1 patient in group M. There was significant improvement in left ventricular ejection fraction (LVEF) in both groups. Moreover, left ventricular size decreased significantly in both groups. In group P, the tethering height, area and papillary muscle distance also decreased significantly. There were no patients who developed recurrent MR postoperatively. However, in group P, there were 2 late deaths caused by congestive heart failure and sepsis, and remaining 3 patients suffered from congestive heart failure. In group M, there were no late deaths and all patients were in New York Heart Association (NYHA) class I or II. CONCLUSION: Our surgical strategy for IMR yields excellent reduction of MR. Especially the PMA provides promising effect on tethering reduction. However, the absence of recurrent MR was not associated with an improvement in symptoms and survival in patients who presented with severe left ventricular dilatation and leaflet tethering.

Topical application of a biodegradable disc with amiodarone for atrial fibrillation.

BACKGROUND: Amiodarone is a potent anti-atrial fibrillation (AF) agent; however, its systemic administration induces serious side effects such as interstitial pneumonia. To avoid such effects, we developed a local sustained-release system for amiodarone. METHODS: A biodegradable, cross-linkable dextran disc was developed as a sustained-release carrier for amiodarone. Under general anesthesia, Japanese white rabbits underwent median sternotomy and the biodegradable disc with or without amiodarone (30 mg) was implanted onto the surface of the right atrium. Three days after implantation, we measured tissue amiodarone concentrations (n = 5), the AF threshold, and the atrial effective refractory period of the left atrium by using the Langendorff apparatus. The incidences of induced AF evoked by rapid pacing were measured and compared. RESULTS: The right atrial concentration of amiodarone was far higher than that in the lungs, ventricles, or other organs (p < 0.01). The blood concentration of amiodarone was below detectable levels. The amiodarone biodegradable disc significantly increased the AF threshold (amiodarone group, 6.9 ± 4.6 mA versus control group, 0.5 ± 0.6 mA; p < 0.01) and the effective refractory period (amiodarone group, 53.9 ± 8.9 milliseconds versus control group, 43.9 ± 9.5 milliseconds; p = 0.035) of the left atrium, indicating the electrophysiologic effect of the amiodarone biodegradable disc on the left atrium. Further, the amiodarone group was significantly less likely to experience AF, as compared with the control group (p < 0.01). CONCLUSIONS: This approach may be a less invasive and effective therapeutic option for preventing postoperative AF.

Excimer laser-assisted retrieval of Günther Tulip vena cava filters: a pilot study in a canine Model.

PURPOSE: Although most Günther Tulip filters (GTFs) can be safely retrieved within a few months after implantation, their recommended safe retrieval period is within a few weeks. This study aims to assess the feasibility of excimer laser-assisted retrieval of GTFs incorporated into the inferior vena cava (IVC) wall in a canine model. MATERIALS AND METHODS: Six GTFs were implanted in six mongrel dogs and retrieved after four weeks. The retrieval system consisted of a 14-F excimer laser sheath, an 8-F guide catheter, and a 15-mm Goose Neck snare. RESULTS: All filters were tightly fixed to the IVC wall. After ablation of the adhesions by excimer laser emission, all filters were successfully retrieved. Final cavography after retrieval revealed no caval damage except for minor extravasation in three dogs. Examination of the caval specimen taken from a dog immediately after filter retrieval revealed partial absence of the intima and media. In the remaining five dogs, cavography performed 2 days after filter retrieval revealed complete hemostasis and almost indistinguishable intimal indentations. On follow-up cavography 28 days after filter retrieval, caval stenosis with 38% +/- 11% diameter narrowing was noted. The caval specimen obtained from a dog at 28 days showed neointima formation at the level where the filter struts were in contact with the caval wall. The other four dogs have survived for more than 3 months without any adverse events. CONCLUSIONS: Laser-assisted retrieval of a GTF incorporated into the IVC wall is feasible in dogs.

A novel approach to prevent spinal cord ischemia: Inoue stent graft with a side branch of small caliber for the reconstruction of the artery of Adamkiewicz.

OBJECTIVES: Paraplegia remains a serious complication after endovascular repair of thoracic aortic aneurysms, and it has been reported that paraplegia might be due to ischemia of the artery of Adamkiewicz. This study investigates the feasibility of an Inoue stent graft with a side branch of a small caliber for the reconstruction of the intercostal artery branching the artery of Adamkiewicz. METHODS: Branched Inoue stent grafts were implanted into the thoracic aorta and 11th intercostal artery of 5 mongrel dogs. The side branch measured 3 x 5 mm and contained a bare-metal coronary stent for fixing to the intercostal arterial wall. Aortography and selective angiography of the 11th intercostal artery were performed before and immediately after implantation and after 1, 4, 8, and 12 weeks. The luminal diameter of the intercostal artery before implantation was 2.4 +/- 0.3 mm. RESULTS: All stent grafts were successfully deployed. The main body of the graft did not develop endoleak or migrate, and the side branch remained patent for 12 weeks. Angiography performed 1 week postoperatively revealed smooth flow with slight stenosis (4.2% +/- 1.7%) along the side branches and the intercostal arteries in all dogs. Four weeks postoperatively, however, mild concentric stenosis (38% +/- 16%) along the side branch was observed in 4 of the 5 dogs. The percent stenosis at 8 and 12 weeks was 38% +/- 15% and 33% +/- 11%, respectively; these values were not significantly different from the value at 4 postoperative weeks. CONCLUSIONS: A novel Inoue stent graft with a side branch of small caliber was successfully deployed into the canine thoracic aorta and intercostal artery; the side branch remained patent for 12 weeks. This novel technique may enable endovascular reconstruction of the Adamkiewicz artery.