Kan Kajimoto

Long-term patency of small-diameter vascular graft made from fibroin, a silk-based biodegradable material

OBJECTIVE There is an increasing need for vascular grafts in the field of surgical revascularization. However, smaller vascular grafts made from synthetic biomaterials, particularly those <5 mm in diameter, are associated with a high incidence of thrombosis. Fibroin is a biodegradable protein derived from silk. Silk fibroin from Bombyx mori provides an antithrombotic surface and serves as a scaffold for various cell types in tissue engineering. We evaluated the potential of fibroin to generate a vascular prosthesis for small arteries. METHODS A small vessel with three layers was woven from silk fibroin thread. These fibroin-based grafts (1.5 mm diameter, 10 mm length) were implanted into the abdominal aorta of 10- to 14-week-old male Sprague-Dawley rats by end-to-end anastomosis. Polytetrafluoroethylene (PTFE)-based grafts were used as the control. To investigate the origin of the cells in the neointima and media, bone marrow transplantation was performed from green fluorescent protein (GFP) rats to wild-type rats. RESULTS The patency of fibroin grafts at 1 year after implantation was significantly higher than that of PTFE grafts (85.1% vs 30%, P < .01). Endothelial cells and smooth muscle cells (SMCs) migrated into the fibroin graft early after implantation and became organized into endothelial and medial layers, as determined by anti-CD31 and anti-alpha-smooth muscle actin immunostaining. The total number of SMCs increased 1.6-fold from 1 month to 3 months. Vasa vasorum also formed in the adventitia. Sirius red staining of the fibroin grafts revealed that the content of collagen significantly increased at 1 year after implantation, with a decrease in fibroin content. GFP-positive cells contributed to organization of a smooth muscle layer. CONCLUSIONS Small-diameter fibroin-based vascular grafts have excellent long-term patency. Bone marrow-derived cells contribute to vascular remodeling after graft implantation. Fibroin might be a promising material to engineer vascular prostheses for small arteries.

Short-term 20-mg atorvastatin therapy reduces key inflammatory factors including c-Jun N-terminal kinase and dendritic cells and matrix metalloproteinase expression in human abdominal aortic aneurysmal wall.

BACKGROUND Abdominal aortic aneurysm (AAA) accumulates features of a chronic inflammatory disorder and irreversible destruction of connective tissue. A recent experimental study identified c-Jun N terminal kinase (JNK) as a proximal signaling molecule in the pathogenesis of AAA and vascular dendritic cells as key players in the inflammatory reaction and degradation of the extracellular matrix. Statins can inhibit cell proliferation and vascular inflammation, which might help prevent AAA progression. However, supporting clinical data from human studies are lacking. We hypothesized that atorvastatin might inhibit JNK and dendritic cells, resulting in suppression of inflammatory cells and matrix metalloproteinases (MMPs) in human tissue of AAA. METHODS Patients with AAA were randomized to atorvastatin (20mg/day, n=10) and non-treated (n=10) groups. After treatment for 4 weeks, patients underwent abdominal aorta replacement, tissue specimens were obtained, and tissue composition was assessed using immunohistochemistry with quantitative image analysis. RESULTS Atorvastatin significantly reduced expression of JNK (1.1% vs. 8.1%, P=0.0002) and dendritic cells (3.2 vs. 7.2, P=0.003) compared to controls. T cells (142 vs. 315, P=0.008), macrophages (13 vs. 24, P=0.048) and immunoreactivity to MMP-2 (7.8% vs. 21%, P=0.049) and MMP-9 (13% vs. 24%, P=0.028) were also suppressed in the atorvastatin group. Serum low-density lipoprotein cholesterol level was decreased by 40% in the atorvastatin group. CONCLUSIONS Atorvastatin treatment acutely reduces JNK expression and dendritic cells, resulting in reduced inflammatory cell content and expression of MMPs in the AAA wall.

Impact of Metabolic Syndrome among Patients with and without Diabetes Mellitus on Long-Term Outcomes after Percutaneous Coronary Intervention

Metabolic syndrome (MS) is highly prevalent and an established key risk factor for coronary artery disease, regardless of the presence or absence of diabetes mellitus (DM). Long-term follow-up studies have addressed the influence of MS with and without DM on the prognosis of patients undergoing percutaneous coronary intervention (PCI). We classified 748 consecutive patients who had undergone PCI into four groups as follows: neither DM nor MS, DM alone, MS alone, and both DM and MS. Post hoc analyses were conducted using prospectively collected clinical data. Multivariate Cox regression was used to evaluate the risk within each group for all-cause mortality and composite cardiac events (cardiac death, non-fatal acute coronary syndrome), adjusting for age, gender, body mass index, low-density lipoprotein (LDL) cholesterol level, hypertension, smoking, prior coronary artery bypass graft, presentation of acute coronary syndrome, left ventricular ejection fraction, multivessel disease, and procedural success. The progress of 321 (42.9%) patients with neither DM nor MS, 109 (14.6%) patients with DM alone, 129 (17.2%) patients with MS alone, and 189 (25.3%) patients with both DM and MS was followed up for a mean of 12.0±3.6 years. Patients with both DM and MS had significant risk for increased all-cause mortality (2.10 [1.19–3.70]). Patients with MS alone (2.14 [1.31–3.50]) and with both DM and MS (1.87 [1.18–2.96]) were at significant risk for increased cardiac events. In conclusion, the risk of cardiac events is significantly increased in patients with metabolic syndrome following PCI, irrespective of DM.

Probucol therapy improves long-term (>10-year) survival after complete revascularization: a propensity analysis.

OBJECTIVE Probucol has anti-atherosclerotic properties and has been shown to reduce post-angioplasty coronary restenosis. However, the effect of probucol therapy on long-term (>10 years) outcome following coronary revascularization is less well established. Accordingly, we sought to determine if probucol therapy at the time of complete coronary revascularization reduces mortality in patients with coronary artery disease (CAD). METHODS We collected data from 1694 consecutive patients who underwent complete revascularization (PCI and/or bypass surgery). Mortality data were compared between patients administered probucol and those not administered probucol at the time of revascularization. A propensity score (PS) was calculated to evaluate the effects of variables related to decisions regarding probucol administration. The association of probucol use and mortality was assessed using 3 Cox regression models, namely, conventional adjustment, covariate adjustment using PS, and matching patients in the probucol and no-probucol groups using PS. RESULTS In the pre-match patients, 231 patients were administered probucol (13.6%). During follow-up [10.2 (SD, 3.2) years], 352 patients died (including 113 patients who died of cardiac-related issues). Probucol use was associated with significant decrease in all-cause death (hazard ratio [HR], 0.65; P=0.036 [conventional adjustment model] and HR, 0.57; P=0.008 [PS adjusted model]). In post-match patients (N=450, 225 matched pair), the risk of all-cause mortality was significantly lower in the probucol group than in the no-probucol group (HR, 0.45; P=0.002). CONCLUSION In CAD patients who had undergone complete revascularization, probucol therapy was associated with a significantly reduced risk of all-cause mortality.

Influence of diabetes on >10-year outcomes after percutaneous coronary intervention

There are few reports showing the relationship between diabetes and the long-term outcome following percutaneous coronary intervention (PCI) in Asians. As well, the association between glycosylated hemoglobin (HbA1c) level and outcome remains controversial. In this analysis, 748 Japanese patients including 298 with diabetes (DM) and 450 without diabetes (non-DM) who underwent PCI from 1984 to 1992 were evaluated over the long term. The mean follow-up was 12.0 ± 3.6 years. There were 47 (15.8%) total deaths in DM and 41 (9.1%) in non-DM [hazard ratio (HR) 1.71, 95% confidence interval (CI) 1.11–2.65, P = 0.013] and 28 (9.4%) cardiovascular deaths in DM and 19 (4.2%) in non-DM (HR 2.09, 95% CI 1.14–3.81, P = 0.016). Among DM, increased HbA1c was associated with both total (HR 1.25, 95% CI 1.03–1.53, P = 0.024) and cardiovascular (HR 1.30, 95% CI 1.00–1.69, P = 0.048) mortality. Even in Asians, DM showed an increased mortality following PCI. Among DM, increased HbA1c level was also associated with mortality.

Metabolic syndrome is an independent risk factor for stroke and acute renal failure after coronary artery bypass grafting.

OBJECTIVES Metabolic syndrome is common among patients having coronary artery bypass grafting. However, it remains unclear whether it has a significant impact on postoperative complications. We aimed to determine whether metabolic syndrome negatively influences the postoperative outcomes of coronary artery bypass grafting. METHODS We enrolled 1183 patients who had coronary artery bypass grafting at Juntendo University Hospital between 1984 and 1992. Patients were categorized by the presence or absence of metabolic syndrome using the modified National Cholesterol Education Program Adult Treatment Panel III definition with body mass index in the place of waist circumference. Multivariate analysis was performed to assess the relationships between preoperative presence of metabolic syndrome and postoperative outcomes. RESULTS Metabolic syndrome was present in 551 (46.6%) patients and absent in 632 (53.4%). Postoperative stroke occurred in 4.7% of patients with metabolic syndrome and 2.1% of patients without metabolic syndrome (P < .0001). Postoperative acute renal failure occurred in 3.8% of patients with metabolic syndrome and 1.1% of patients without metabolic syndrome. On multivariate analysis, metabolic syndrome had odds ratios of 2.47 (95% confidence interval 1.22-4.99; P = .012) for postoperative stroke and 3.81 (95% confidence interval 1.42-10.3; P = .008) for postoperative acute renal failure. CONCLUSIONS This study showed the clinical importance of metabolic syndrome with respect to postoperative stroke and acute renal failure in patients having coronary artery bypass grafting. Like many established risk factors for postoperative complications, metabolic syndrome should be recognized as a novel risk factor for adverse events.

Prognostic impact of chronic kidney disease on 10-year clinical outcomes among patients with acute coronary syndrome

BACKGROUND Chronic kidney disease (CKD) is closely associated with a higher risk of cardiovascular disease. However, whether patients with acute coronary syndrome (ACS) and CKD are at increased risk for long-term mortality after coronary revascularization remains unknown. METHODS AND RESULTS Data from consecutive patients with ACS who had undergone coronary revascularization, including percutaneous coronary intervention (PCI) and coronary artery bypass surgery (CABG) were analyzed. The estimated glomerular filtration rate (eGFR) was calculated using the current Japanese equation and CKD was defined as eGFR < 60 mL/min/1.73 m(2). Among 375 enrolled patients with ACS, 75 (20.0%) had CKD. During a follow-up period of 10.0 ± 3.4 years, the total number of deaths was 80 (21.3%), of which 36 (9.6%) were due to cardiovascular causes. Kaplan-Meier analysis showed that the presence of CKD was associated with a significant increase in mortality from all causes (log-rank test, p<0.001) and cardiovascular mortality (p<0.001). Cox proportional-hazard analysis revealed that CKD increased the risk of mortality with a hazard ratio of 2.31 (95% confidence interval (CI): 1.25-4.29, p=0.008) and of cardiovascular death with a hazard ratio of 3.76 (95% CI: 1.60-8.80, p=0.002) in patients with ACS. CONCLUSIONS CKD is a powerful determinant of long-term all-cause and cardiovascular mortality after ACS.

Therapy with statins and aspirin enhances long-term outcome of percutaneous coronary intervention

Aspirin is the standard therapy applied after coronary intervention, and statins are also prescribed to prevent secondary coronary heart disease. We assessed the ability of a combination of statins and aspirin to improve the longterm prognosis of patients after percutaneous coronary intervention (PCI). We collected data from 575 consecutive patients who underwent PCI. The patients were divided into groups depending on the presence or absence of statin or aspirin therapy as follows: both statin and aspirin (Group B: n = 190; 33%); aspirin only (Group A: n = 236; 41.1%); statin only (Group S: n = 53; 9.2%S); neither drug (Group N: n = 96; 16.7%). Data were statistically assessed using the Cox proportional hazard model for multivariate analysis with adjustment of baseline convariates. Sixty-eight patients died during follow-up (11 ± 3 years). Multivariate analysis showed that compared with group N, both groups S and A were independent predictors for survival from all causes [group S: hazards ratio (HR) 0.29, 95% confidence interval (CI) 0.10–0.81, P = 0.019; group A: HR 0.31, 95% CI 0.17–0.56, P < 0.0001] and cardiovascular (CV) death (group S: HR 0.16, 95% CI 0.04–0.73, P = 0.018; group A: HR 0.12, 95% CI 0.05–0.30, P < 0.001). risk for all causes and CV death was significantly lower in Group B (HR 0.25, 95% CI 0.12–0.53, P < 0.0001 and HR 0.10, 95% CI 0.03–0.31, P < 0.0001, respectively). Therapy with statins plus aspirin improves long-term clinical outcome in patients after PCI.

Mortality risk of triglyceride levels in patients with coronary artery disease

Objective The association between triglyceride level and the risk of coronary artery disease (CAD) remains controversial. In particular, the prognostic significance of triglyceride levels in established CAD is unclear. We aimed to assess the relationship between triglyceride levels and long-term (>10 years) prognosis in a cohort of patients after complete coronary revascularisation. Design Observational cohort study. Setting Departments of cardiology and cardiovascular surgery in a university hospital. Patients Consecutive patients who had undergone complete revascularisation between 1984 and 1992. All patients were categorised according to the quintiles of fasting triglyceride levels at baseline. Main outcome measures The risk of fasting triglyceride levels for all-cause and cardiac mortality was assessed by multivariable Cox proportional hazards regression analyses. Results Data from 1836 eligible patients were assessed. There were 412 (22.4%) all-cause deaths and 131 (7.2%) cardiac deaths during a median follow-up of 10.5 years. Multivariable analyses including total and high-density lipoprotein cholesterol and other covariates revealed no significant differences in linear trends for all-cause mortality according to the quintiles of triglyceride (p for trend=0.711). However, the HR increased with the triglyceride levels in a significant and dose-dependent manner for cardiac mortality (p for trend=0.031). Multivariable analysis therefore showed a significant relationship between triglyceride levels, when treated as a natural logarithm-transformed continuous variable, and increased cardiac mortality (HR 1.51, p=0.044). Conclusions Elevated fasting triglyceride level is associated with increased risk of cardiac death after complete coronary revascularisation.

Comparing outcomes after off-pump coronary artery bypass versus drug-eluting stent in diabetic patients

BACKGROUND Off-pump coronary artery bypass surgery and sirolimus-eluting stent placement have been widely used for the treatment of coronary artery disease. The goal of this study was to compare long-term outcomes after off-pump coronary artery bypass surgery or sirolimus-eluting stent placement in diabetic patients with multivessel disease. METHODS This observational study enrolled 350 off-pump coronary artery bypass patients and 143 sirolimus-eluting stent patients receiving care at our institution between 2000 and 2007. All patients had diabetes and multivessel disease including proximal left anterior descending or left main coronary artery. The choice of revascularization (percutaneous coronary intervention versus coronary artery bypass surgery) was left to the physicians discretion rather than randomization. Cox proportional-hazard analyses, adjusting baseline risk factors and propensity score, which predicted the probability of receiving off-pump coronary artery bypass, were conducted to evaluate outcomes, including all-cause mortality, cardiac death, target vessel revascularization, and major adverse cardiac and cerebrovascular events. RESULTS During the follow-up (2.6±1.6 years) period, there was no difference between off-pump coronary artery bypass and sirolimus-eluting stent placement in all-cause mortality or cardiac death. However, the incidences of acute coronary syndrome, target vessel revascularization, and major adverse cardiac and cerebrovascular events were markedly lower in the patients undergoing off-pump coronary artery bypass than in those receiving sirolimus-eluting stent placement. CONCLUSION Off-pump coronary artery bypass is superior to sirolimus-eluting stent placement in terms of acute coronary syndrome, target vessel revascularization, and major adverse cardiac and cerebrovascular events in diabetic patients with multivessel coronary artery disease.