Yu Jen Yang

Intramyocardial Peptide Nanofiber Injection Improves Postinfarction Ventricular Remodeling and Efficacy of Bone Marrow Cell Therapy in Pigs

Background— Growing evidence suggests that intramyocardial biomaterial injection improves cardiac functions after myocardial infarction (MI) in rodents. Cell therapy is another promising approach to treat MI, although poor retention of transplanted cells is a major challenge. In this study, we hypothesized that intramyocardial injection of self-assembling peptide nanofibers (NFs) thickens the infarcted myocardium and increases transplanted autologous bone marrow mononuclear cell (MNC) retention to attenuate cardiac remodeling and dysfunction in a pig MI model. Methods and Results— A total of 40 mature minipigs were divided into 5 groups: sham, MI+normal saline, MI+NFs, MI+MNCs, and MI+MNCs/NFs. MI was induced by coronary occlusion followed by intramyocardial injection of 2 mL normal saline or 1% NFs with or without 1×108 isolated autologous MNCs. NF injection significantly improved diastolic function and reduced ventricular remodeling 28 days after treatment. Injection of MNCs alone ameliorated systolic function only, whereas injection of MNCs with NFs significantly improved both systolic and diastolic functions as indicated by +dP/dt and −dP/dt (1214.5±91.9 and −1109.7±91.2 mm Hg/s in MI+NS, 1693.7±84.7 and −1809.6±264.3 mm Hg/s in MI+MNCs/NFs, respectively), increased transplanted cell retention (29.3±4.5 cells/mm2 in MI+MNCs and 229.4±41.4 cells/mm2 in MI+MNCs/NFs) and promoted capillary density in the peri-infarct area. Conclusions— We demonstrated that NF injection alone prevents ventricular remodeling, whereas cell implantation with NFs improves cell retention and cardiac functions after MI in pigs. This unprecedented combined treatment in a large animal model has therapeutic effects, which can be translated to clinical applications in the foreseeable future.

In situ reconstruction of septic aortic pseudoaneurysm due to Salmonella or Streptococcus microbial aortitis: long-term follow-up.

OBJECTIVE This study was undertaken to illustrate the safety of in situ reconstruction of septic aortic pseudoaneurysm (SAP) secondary to microbial aortitis, with or without long-term antibiotic treatment. METHODS Data for patients with SAP (11 abdominal, 4 thoracic) operated on between 1993 and 1999 were reviewed. Computed tomography and aortography showed septic pseudoaneurysm in all patients before surgery. After diagnosis of SAP, all patients underwent aneurysm resection and extensive debridement, with in situ prosthetic grafting or patch repair angioplasty. The graft in 10 of the 11 patients with abdominal SAP was also wrapped with an omental pedicle. In vitro active parenteral antibiotic therapy was prescribed for all patients for at least 2 to 8 weeks after surgery. RESULTS All 15 patients had positive preoperative blood cultures or intraoperative tissue cultures for Salmonella spp (n = 12), viridans Streptococcus (n = 1), group G Streptococcus (n = 1), or Streptococcus pneumoniae (n = 1). There were two perioperative deaths (13.3%), one 6 days after surgery and the other 19 days after surgery, and two late deaths, at 8 and 10 months after surgery, neither of which was related to aortic repair. One patient was unavailable for follow-up. The other 10 patients have been regularly followed up with abdominal ultrasound or computed tomography (mean, 84 months; range, 47-118 months). To date, there has been no graft infection, thrombosis, false aneurysm, or subsequent aortic surgery in these 10 patients. CONCLUSION SAP due to Salmonella and streptococcal microbial aortitis can be successfully treated with resection of the aneurysm and extensive debridement, followed by in situ prosthetic graft interposition or patch repair aortoplasty. This is a safe and effective treatment that may result in complete remission of SAP. Postoperative parenteral antibiotic therapy should be continued for 2 to 8 weeks. Although usually recommended, lifelong suppressive antibiotic therapy appears to be nonessential with this approach.

Functionalized nanoparticles provide early cardioprotection after acute myocardial infarction.

Recent developments in nanotechnology have created considerable potential toward diagnosis and cancer therapy. In contrast, the use of nanotechnology in tissue repair or regeneration remains largely unexplored. We hypothesized that intramyocardial injection of insulin-like growth factor (IGF)-1-complexed poly(D,L-lactide-co-glycolide) (PLGA) nanoparticles (PLGA-IGF-1 NPs) increases IGF-1 retention, induces Akt phosphorylation, and provides early cardioprotection after acute myocardial infarction (MI). We synthesized 3 different sizes of PLGA particles (60 nm, 200 nm, and 1 μm) which were complexed with IGF-1 using electrostatic force to preserve the biological function of IGF-1. Afterward, we injected PLGA-IGF-1 NPs in the heart after MI directly. Compared with the other two larger particles, the 60 nm-sized PLGA-IGF-1 NPs carried more IGF-1 and induced more Akt phosphorylation in cultured cardiomyocytes. PLGA-IGF-1 NPs also prolonged Akt activation in cardiomyocytes up to 24h and prevented cardiomyocyte apoptosis induced by doxorubicin in a dose-dependent manner. In vivo, PLGA-IGF-1 NP treatment significantly retained more IGF-1 in the myocardium than the IGF-1 alone treatment at 2, 6, 8, and 24 h. Akt phosphorylation was detected in cardiomyocytes 24h post-MI only in hearts receiving PLGA-IGF-1 NP treatment, but not in hearts receiving injection of PBS, IGF-1 or PLGA NPs. Importantly, a single intramyocardial injection of PLGA-IGF-1 NPs was sufficient to prevent cardiomyocyte apoptosis (P<0.001), reduce infarct size (P<0.05), and improve left ventricle ejection fraction (P<0.01) 21 days after experimental MI in mice. Our results not only demonstrate the potential of nanoparticle-based technology as a new approach to treating MI, but also have significant implications for translation of this technology into clinical therapy for ischemic cardiovascular diseases.

The Efficacy of Aortic Stent Grafts in the Management of Mycotic Abdominal Aortic Aneurysm-Institute Case Management with Systemic Literature Comparison

BACKGROUND Conventional surgery (CS) for treatment of mycotic aortic aneurysm has rather high surgical morbidity and mortality rates. The use of endovascular aortic repair (EVAR) might simplify the procedure and provide a good alternative for this critical condition, but this remains to be proved. We analyzed all mycotic abdominal aortic aneurysm (AAA) cases treated by CS or EVAR in our institute and the reported cases treated by EVAR from the literature to determine the risk factors for aneurysm-related mortality and morbidity and to clarify the efficacy of the EVAR technique. METHODS AND RESULTS All relevant literature reports of EVAR management of mycotic AAA and all cases treated in our institute, 41 cases, were included and analyzed. Of the 20 cases treated by EVAR, one had early mortality (1/20, 5%); of the remaining 21 cases that received CS, the early mortality rate was 4.8% (1/21). Patients in the CS group had a higher late mortality rate than those in the EVAR group (45% vs. 10.5%, p<0.05). However, the 24-month actual survival rate and actuarial aneurysm-related event-free rate were 83.9+/-8.6% and 78.3+/-9.7%, respectively, for the EVAR group and did not significantly differ from the CS group (70.4+/-10.2% and 80.1+/-8.9%). The significant predictors for aneurysm-related mortality and morbidity were age, Salmonella species infection, and leukocytosis, and possibly aortoenteric fistula and shock, but not the EVAR or CS procedures themselves. CONCLUSION Compared with CS, EVAR might be an alternative strategy for managing mycotic AAAs.

The feasibility of endovascular aortic repair strategy in treating infected aortic aneurysms

BACKGROUND Open surgical treatment for an infected aortic aneurysm has a high rate of surgical morbidity and mortality and does not guarantee eradication of the infected nidus. The use of endovascular aortic repair (EVAR) might simplify the procedure and provide a good alternative for this critical condition, but this remains to be proved. This study assessed the efficacy and outcome of EVAR with an adjunctive antibiotic treatment strategy. METHODS We focused on the experiences and results of the management of infected aortic aneurysms with positive blood cultures. We drew the blood for culture study, immediately prescribed broad-spectrum antibiotics, performed EVAR procedures, and followed this with sensitive antibiotics and adjunctive procedures. RESULTS Twelve consecutive patients (mean age, 70 years) were included in this EVAR strategy. Three patients had thoracic, two thoracoabdominal, and the remaining seven had infected abdominal aneurysms. Ten Salmonella, one Staphylococcus, and one Streptococcus spp were identified. There was no hospital death. Three patients underwent computed tomography (CT)-guided drainage, and one underwent open laparotomy debridement. Mean follow-up was 24 months. One late death occurred but was unrelated to reinfection. All patients seemed well, with no evidence of EVAR graft infection at a mean follow-up of 23.6 months. CONCLUSIONS This small multi-institutional study summarizing the experiences of patients with an infected aortic aneurysm managed by EVAR and an aggressive antibiotic strategy revealed that this EVAR strategy might be a suitable approach to treating this disease. These favorable results may be typical for Salmonella infection, which was present in most of the patients. Further experience is needed to assess whether this therapeutic strategy works equally well in aneurysm infection caused by other organisms.

Fatao coxsackievirus B infection in early infancy characterized by fulminant hepatitis

OBJECTIVES to clarify the major features of fatal coxsackievirus B infection characterized by fulminant hepatitis in early infancy. METHODS clinical manifestations and laboratory investigations concerning five consecutive young infants with overwhelming coxsackievirus B fulminant hepatitis between 1994 and 1997 were retrospectively reviewed. Aetiological diagnosis was made by viral cultures and confirmed by a neutralization test with a type-specific antiserum. RESULTS all five had a deteriorating clinical course of severe hepatitis complicated by disseminated intravascular coagulopathy (DIC). Coxsackievirus B1 infection was established in four patients and coxsackievirus B3 in one. The pathological findings of the two cases illustrated extensive hepatocellular necrosis. Fulminant hepatitis can occur as a leading presentation of disseminated coxsackievirus B infections and dominant the clinical features in neonates and young infants. CONCLUSIONS the liver was the target organ of fatal coxsackievirus B infection in our patients. Hepatic involvement progressed rapidly to jaundice and coagulopathy, and was considered to be indicative of poor prognosis. Coxsackievirus B hepatitis may be serious in early infancy.

Prosthetic valve endocarditis caused by Streptobacillus moniliformis: a case of rat bite fever.

ABSTRACT We report a case of rat bite fever caused by Streptobacillus moniliformis in Taiwan. It manifested as prosthetic valve endocarditis, which was cured by cardiac valve replacement and antimicrobial therapy. The DNA sequence of the 16S rRNA gene of S. moniliformis was detected in valve specimens by PCR and nucleotide sequencing.

Bilateral Persistent Sciatic Arteries Complicated with Acute Left Lower Limb Ischemia

Persistent sciatic artery (PSA) is a rare congenital malformation. In the early embryonic stage, the sciatic artery is the major blood supply for the lower limb bulb and is later replaced by the iliofemoral artery as the limb develops. Its failure to regress, sometimes associated with femoral arterial hypoplasia, and therefore becoming the dominant inflow to the lower extremity is called PSA. This anomaly is often associated with a higher rate of aneurysm formation or thromboembolic complications causing lower extremity ischemia. Here, we describe a 79-year-old male patient who presented with acute left lower extremity ischemia. He was treated initially with conventional embolectomy through inguinal and popliteal incisions. The bilateral PSA with thrombosed aneurysms was not identified at first on computed tomographic angiography. It was later diagnosed intraoperatively due to the discontinuity of the superficial femoral artery and popliteal artery found with embolectomy catheter, and was managed successfully with ePTFE graft bypass. Careful interpretation of the imaging study may be helpful in preoperative diagnosis.

Effect of false lumen partial thrombosis on repaired acute type A aortic dissection

OBJECTIVE Studies on the partial thrombosis of a false lumen after repairing a type A acute aortic dissection (TAAAD) have reported conflicting results. We investigated the effects of a partially thrombosed false lumen on the segmental growth rates, distal aortic reoperations, and long-term survival. METHODS The postoperative computed tomography scans of 67 patients were retrospectively reviewed. A false lumen was independently defined at 3 segments of the descending thoracic aorta (DTA) on the last follow-up computed tomography scan: the proximal segment near the aortic arch, the distal segment near the diaphragm, and the middle segment. RESULTS The segmental aortic growth rate of completely thrombosed, completely patent, and partially thrombosed false lumens was -0.10±0.31, 0.09±0.22, and 0.35±0.60 mm/mo at the proximal DTA (P=.001), -0.04±0.18, 0.12±0.19, and 0.28±0.28 mm/mo at the middle DTA (P<.001), and -0.02±0.13, 0.07±0.07, and 0.16±0.14 mm/mo at the distal DTA (P<.001), respectively. The corresponding freedom from reoperation rates for the proximal DTA at 10 years were 100%, 88%, and 62% (P=.013). The overall 10-year survival rate was 89% and was not significantly different among the study groups. CONCLUSIONS Partial thrombosis at each segment of a residual false lumen after TAAAD repair correlated with a faster regional aortic growth rate and predicted a greater reoperation rate but did not affect long-term overall survival.

Recombinant human thrombomodulin suppresses experimental abdominal aortic aneurysms induced by calcium chloride in mice

Objective: To investigate whether recombinant thrombomodulin containing all the extracellular domains (rTMD123) has therapeutic potential against aneurysm development. Summary Background Data: The pathogenesis of abdominal aortic aneurysm (AAA) is characterized by chronic inflammation and proteolytic degradation of extracellular matrix. Thrombomodulin, a transmembrane glycoprotein, exerts anti-inflammatory activities such as inhibition of cytokine production and sequestration of proinflammatory high-mobility group box 1 (HMGB1) to prevent it from engaging the receptor for advanced glycation end product (RAGE) that may sustain inflammation and tissue damage. Methods: The in vivo effects of treatment and posttreatment with rTMD123 on aortic dilatation were measured using the CaCl2-induced AAA model in mice. Results: Characterization of the CaCl2-induced model revealed that HMGB1 and RAGE, both localized mainly to macrophages, were persistently upregulated during a 28-day period of AAA development. In vitro, rTMD123-HMGB1 interaction prevented HMGB1 binding to macrophages, thereby prohibiting activation of HMGB1-RAGE signaling in macrophages. In vivo, short-term treatment with rTMD123 upon AAA induction suppressed the levels of proinflammatory cytokines, HMGB1, and RAGE in the aortic tissue; reduced the infiltrating macrophage number; and finally attenuated matrix metalloproteinase production, extracellular matrix destruction, and AAA formation without disturbing vascular calcification. Consistently, posttreatment with rTMD123 seven days after AAA induction alleviated vascular inflammation and retarded AAA progression. Conclusions: These data suggest that rTMD123 confers protection against AAA development. The mechanism of action may be associated with reduction of proinflammatory mediators, blockade of macrophage recruitment, and suppression of HMGB1-RAGE signaling involved in aneurysm formation and downstream macrophage activation.