In vivo optical coherence tomography visualisation of coronary artery embolism caused by BioGlue in a middle-aged woman with Marfan syndrome who underwent the Bentall procedure: a case report.

Background: Coronary artery embolism caused by BioGlue is a rare complication; therefore, its diagnosis and treatment remain undefined. Case summary: A 47-year-old woman underwent ascending aortic replacement and coronary artery bypass grafting (CABG) for type A acute aortic dissection involving the right coronary artery ostium in 2017. Subsequently, she was diagnosed with Marfan syndrome. Five years later in 2022, she underwent aortic arch replacement, the Bentall procedure, and repeat CABG because of aortic root enlargement and aortic regurgitation progression. Twelve days after surgery, coronary computed tomography angiography (CCTA) revealed left anterior descending (LAD) artery stenosis, whereas pre-operative CCTA was normal. On post-operative day 13, coronary angiography revealed 99% LAD artery stenosis. Intravascular ultrasound (IVUS) showed a non-echoic mass with clear margins, and optical coherence tomography (OCT) demonstrated a crystalloid mass. Both images suggested that the embolus was inorganic matter, suspected as being the surgical adhesive BioGlue. We could not remove the embolus by repeated thrombectomy; therefore, drug-eluting stent implantation was performed. Seven months after surgery, she had no symptoms, and CCTA confirmed stent patency. Discussion: To our knowledge, this is the first case report to describe BioGlue embolism observed by OCT. We performed an in vitro study using a blood vessel model, and the obtained OCT image was very similar to the in vivo image. Although BioGlue embolism is a rare complication, it should be considered in cases of perioperative myocardial infarction of uncertain aetiology, and coronary imaging is useful for diagnosis.

Successful Transcatheter Aortic Valve Implantation in a Patient with Radiation-induced Aortic Stenosis for Mediastinal Hodgkin Lymphoma.

Aortic stenosis (AS), a late complication of thoracic radiation therapy for chest lesions, is often coincident with porcelain aorta or hostile thorax. We herein report a 59-year-old man with a history of mediastinal Hodgkin lymphoma treated with radiation therapy but later presenting with heart failure caused by severe AS. Severe calcification in the mediastinum and around the ascending aorta made it difficult to perform surgical aortic valve replacement. The patient therefore underwent transcatheter aortic valve implantation (TAVI). It is important to recognize radiation-induced AS early, now that TAVI is a well-established treatment required by increasing numbers of successfully treated cancer patients.

Relationship between left ventricular diastolic dysfunction and very late recurrences after multiple procedures for atrial fibrillation ablation.

Although very late recurrences (VLRs) (first recurrence >12 months after the last catheter ablation) of atrial fibrillation (AF) after multiple catheter ablation procedures are rare, it remains a critical issue. The risk factors for VLRs remain largely unclear. From December 2011 to April 2014, 253 patients underwent an initial catheter ablation. Of the 253 patients, 21 had AF recurrences within 1 year after the last catheter ablation. The study was conducted in the remaining 232 patients. Left ventricular diastolic dysfunction (LVDD) was assessed by echocardiography using composite categories with tissue Doppler imaging and left atrial volume measurements, i.e., a septal e' < 8 cm/s, lateral e' < 10 cm/s, and left atrium volume index (LAV/body surface area) (LAVI) ≥34 mL/m2. LVDD was observed in 40 patients. Sinus rhythm was preserved in 220 patients after multiple catheter procedures, and 12 had VLRs. The clinical factors possibly related to VLRs were examined, and a multivariate regression analysis showed that LVDD was the only independent risk factor for VLRs (hazard ratio: 10.31, 95% confidence interval: 2.78-38.18, P < 0.0001). LVDD at baseline is a risk factor for a VLR after multiple catheter ablation procedures for AF.

Predictors of Prognosis in Light-Chain Amyloidosis and Chronological Changes in Cardiac Morphology and Function.

Immune light-chain (AL) amyloidosis with cardiac involvement is associated with a high mortality despite improved therapeutic regimens, but there are few reports on prognostic predictors and chronological changes in cardiac morphology and function. Prognosis and its predictors were evaluated in 36 consecutive patients with cardiac AL amyloidosis. Chronological changes in cardiac morphology and function were also evaluated. The median follow-up period was 0.95 years. The median survival time and the 3-year death-free rate after diagnosis in all-cause and cardiac deaths were 0.85 and 1.06 years and 26% and 36%, respectively. Differences in the median survival time due to left ventricular (LV) wall thickness at diagnosis were not evident. Being female and diastolic wall strain (DWS), as a measure of diastolic stiffness, were independent predictors of all-cause death in the multivariable analysis. The receiver operating characteristic analysis revealed that a DWS cut-off value of 0.189 had a sensitivity of 78% and a specificity of 72% for predicting all-cause death within 1 year after diagnosis (area under the curve = 0.726). The LV size and the stroke volume decreased and DWS worsened during the short-term follow-up period in patients who died within 1 year compared with patients who were alive after 1 year. The prognosis for patients with cardiac AL amyloidosis was poor, and DWS may be a significant predictor of prognosis. Narrowing of the LV cavity and progressive diastolic dysfunction were evident in patients with a poor prognosis.

Diagnostic accuracy of the Embolic Risk French Calculator for symptomatic embolism with infective endocarditis among Japanese population.

BACKGROUND: Recently, the Embolic Risk French Calculator (ER-Calculator) was designed to predict symptomatic embolism (SE) associated with infective endocarditis (IE), but external validation has not been reported. This study aimed to determine predictors of SE and the diagnostic accuracy of the ER-Calculator in left-sided active IE among a Japanese population. METHODS: This retrospective cohort study included 166 consecutive patients with a definite diagnosis of left-sided IE from 1994 to 2015 in our institution. SE during the period after initiation of antibiotic therapy was defined as new SE and embolism during the period before initiation of antibiotic therapy was defined as previous embolism. The primary endpoint was new SE. RESULTS: The mean age of patients was 63±17 years. New SE occurred in 23 (14%) patients at a median of 6 days (interquartile range: 2.5-12.5 days) after initiation of antibiotic therapy. The cumulative incidence of new SE at 12 weeks was 18.2%. The 2-week probability by the ER-Calculator as well as previously reported predictors, such as previous embolism, vegetation length (>10mm), and their combination, were associated with a high risk of new SE. By receiver operating characteristic analysis, the area under the curve of the 2-week probability by the ER-Calculator for prediction of new SE was 0.75 and the optimal cut-off value was 8%. A 2-week probability >8% by the ER-Calculator was the most useful predictor of new SE (hazard ratio 3.63, 95% confidence interval 1.50-8.37; p=0.006), which was more remarkable for fatal embolic events (hazard ratio 13.9, 95% confidence interval 3.19-95.4; p=0.004). CONCLUSIONS: The ER-Calculator is a useful predictor of new SE. Predictive ability is more remarkable for critical embolic events.

Risk Factors of Aortic Plaque Progression Evaluated by Long-Term Follow-Up Data With Transesophageal Echocardiography.

There are few longitudinal data regarding aortic plaque. This study aimed to examine chronological changes in aortic plaques with transesophageal echocardiography (TEE), and to clarify the risk factors of aortic plaque progression. Among 2,675 consecutive patients who underwent TEE, we retrospectively investigated 252 patients who underwent follow-up TEE with an interval >3 years. The thickness and morphology of aortic plaques were examined. Chronological changes in aortic plaques were investigated by comparing baseline and follow-up TEE. Clinical factors, laboratory data, and medications were evaluated. Among 252 study patients, the grade of aortic plaques was unchanged in 213 (group U), but progression was observed in 32 (group P) and regression in 7 patients (group R). Patients in group P were older; they had a higher prevalence of coronary artery disease, hypertension, smoking habit, and moderate or severe plaque at baseline TEE; more patients were using statins and no warfarin; and they had higher creatinine levels than those in group U. In multivariate analysis, moderate or severe plaques at baseline TEE were the strongest predictor of plaque progression. Among 50 patients who showed moderate or severe plaque at baseline TEE, smoking habit and no anticoagulation therapy were predictors of plaque progression. In conclusion, aortic plaques should be followed up using TEE in patients with moderate or severe plaque at baseline TEE.

Long-Term Clinical Outcomes and Prognostic Factors After Pericardiectomy for Constrictive Pericarditis in a Japanese Population.

BACKGROUND: Constrictive pericarditis (CP) is characterized by impaired diastolic cardiac function leading to heart failure. Pericardiectomy is considered effective treatment for CP, but data on long-term clinical outcomes after pericardiectomy are limited.Methods and Results:We retrospectively investigated 45 consecutive patients (mean age, 59±14 years) who underwent pericardiectomy for CP. Preoperative clinical factors, parameters of cardiac catheterization, and cardiac events were examined. Cardiac events were defined as hospitalization owing to heart failure or cardiac death.Median follow-up was 5.7 years. CP etiology was idiopathic in 16 patients, post-cardiac surgery (CS) in 21, tuberculosis-related in 4, non-tuberculosis infection-related in 2, infarction-related in 1, and post-radiation in 1. The 5-year event-free survival was 65%. Patients with idiopathic CP and tuberculosis-related CP had favorable outcomes compared with post-CS CP (5-year event-free survival: idiopathic, 80%; tuberculosis, 100%; post-CS, 52%). Higher age (hazard ratio: 2.51), preoperative atrial fibrillation (3.25), advanced New York Heart Association class (3.92), and increased pulmonary artery pressure (1.06) were predictors of cardiac events. Patients with postoperative right-atrial pressure ≥9 mmHg had lower event-free survival than those with right-atrial pressure <9 mmHg (39% vs. 75% at 5 years, P=0.013). CONCLUSIONS: Long-term clinical outcomes after pericardiectomy among a Japanese population were related to the underlying etiology and the patient's preoperative clinical condition. Postoperative cardiac catheterization may be helpful in the prediction of prognosis after pericardiectomy.

Late recurrence of left ventricular dysfunction after aortic valve replacement for severe chronic aortic regurgitation.

BACKGROUND: Aortic valve replacement (AVR) for chronic aortic regurgitation (AR) with a decreased ejection fraction (EF) leads to improvement in left ventricular (LV) function, but there are no reports on late recurrence of LV dysfunction over long-term after AVR. This study aimed to identify frequency and predictors of late recurrent LV dysfunction after AVR. METHODS: We retrospectively investigated 58 consecutive patients undergoing AVR for severe chronic AR and with follow-up echocardiography for >5years after AVR. Late recurrence of LV dysfunction was defined as an EF of <50% late after AVR and a 10% reduction in the EF compared with that observed at 1year after AVR. RESULTS: The mean follow-up period was 10.3±5.2years. The preoperative EF was <50% in 21 (36%) patients, but it was normalized at 1year after AVR in all patients except for one. However, late recurrence of LV dysfunction developed in 7 (12%) of the 58 patients. These patients showed significantly higher LV end-diastolic and end-systolic diameters before and at 1year after AVR, a lower EF and relative wall thickness before AVR, a higher LV mass index at 1year after AVR, and a higher incidence of preoperative and postoperative atrial fibrillation than those without late recurrence. CONCLUSIONS: Late recurrent LV dysfunction may occur after AVR for severe chronic AR despite EF being once normalized. Early surgery proceeding remarkable LV enlargement and maintaining sinus rhythm are important for LV function over the long-term after AVR.

The Influence of Assay Selection on Prothrombin Time Measured in Patients Treated With Rivaroxaban for Nonvalvular Atrial Fibrillation.

BACKGROUND: Prothrombin time (PT) can provide a qualitative assessment of the relative intensity of anticoagulation by rivaroxaban. More than ten types of assay are available for the measurement of PT in clinical settings, but it is not yet fully understood whether their interactions with rivaroxaban are uniform or inconsistent. METHODS: We examined 139 blood samples from patients taking rivaroxaban. We measured PT using five different commercially available assays. We also evaluated the estimated rivaroxaban concentration using a chromogenic anti-factor Xa assay. RESULTS: The median estimated concentration of rivaroxaban was 192 ng/ml (interquartile range 85-284 ng/ml). The correlation coefficient (r) between PT and the estimated concentrations of rivaroxaban was as follows: Thromborel S, r = 0.768; Thrombocheck PT, r = 0.861; Coagpia PT-N, r = 0.909; Neoplastin Plus, r = 0.882; and Triniclot PT Excel S, r = 0.870. The gradients of the regression plots differed more than fourfold, and the standard deviation of the regression line ranged from 1.001 to 2.980, which tended to be higher for the assays with the higher regression slope gradients. CONCLUSION: The estimated concentration of rivaroxaban varied greatly depending on the assay, so the PT measured in patients taking rivaroxaban should be interpreted with caution.

Detecting Cardiac Sarcoidosis with a Right Atrial Mass Using Transthoracic Echocardiography.

An asymptomatic 40-year-old woman with a first-degree atrioventricular block presented a right atrial mass in transthoracic echocardiograms. Transesophageal echocardiograms showed abnormally thickened tissue on the interatrial septum, which extended around the aortic annulus. Multimodality examinations demonstrated lesions in the heart, lungs, liver, and spleen, suggesting sarcoidosis. She was diagnosed with cardiac sarcoidosis after we detected granulomas in a lung specimen. A right atrial mass shrunk following steroid therapy. We should therefore consider the possibility of cardiac sarcoidosis when we see wall thickening and a mass echo in the atrium. These signs may point to an early-phase lesion of cardiac sarcoidosis.

The ATP-binding cassette transporter ABCG2 protects against pressure overload-induced cardiac hypertrophy and heart failure by promoting angiogenesis and antioxidant response.

OBJECTIVE: ATP-binding cassette transporter subfamily G member 2 (ABCG2), expressed in microvascular endothelial cells in the heart, has been suggested to regulate several tissue defense mechanisms. This study was performed to elucidate its role in pressure overload-induced cardiac hypertrophy. METHODS AND RESULTS: Pressure overload was induced in 8- to 12-week-old wild-type and Abcg2-/- mice by transverse aortic constriction (TAC). Abcg2-/- mice showed exaggerated cardiac hypertrophy and ventricular remodeling after TAC compared with wild-type mice. In the early phase after TAC, functional impairment in angiogenesis and antioxidant response in myocardium was found in Abcg2-/- mice. In vitro experiments demonstrated that ABCG2 regulates transport of glutathione, an important endogenous antioxidant, from microvascular endothelial cells. Besides, glutathione transported from microvascular endothelial cells in ABCG2-dependent manner ameliorated oxidative stress-induced cardiomyocyte hypertrophy. In vivo, glutathione levels in plasma and the heart were increased in wild-type mice but not in Abcg2-/- mice after TAC. Treatment with the superoxide dismutase mimetic ameliorated cardiac hypertrophy in Abcg2-/- mice after TAC to the same extent as that in wild-type mice, although cardiac dysfunction with impaired angiogenesis was observed in Abcg2-/- mice. CONCLUSION: ABCG2 protects against pressure overload-induced cardiac hypertrophy and heart failure by promoting angiogenesis and antioxidant response.

The angiotensin receptor blocker, telmisartan, reduces and stabilizes atherosclerosis in ApoE and AT1aR double deficient mice.

The renin-angiotensin system (RAS) plays critical roles in the pathogenesis of atherosclerosis. Clinical studies demonstrate that pharmacological blockade of RAS with Angiotensin II type 1 receptor (AT1R) blockers (ARBs) is effective in the treatment of patients with cardiovascular diseases. Recent studies reported that telmisartan, an ARB, has a partial agonistic effect on peroxisome proliferator-activated receptor-gamma (PPAR-γ). The role of PPAR-γ-mediated signaling has been implicated in regulation of not only metabolic disorders but also atherosclerosis. Here, we investigated the effects of telmisartan, which is not related to AT1R blockade, using AT1aR and apolipoprotein E (ApoE) double-deficient (ApoE-/-AT1R-/-) mice in vivo. Both genetic ablation of AT1R in ApoE-deficient (ApoE-/-) mice and administration of telmisartan (10 mg/kg/day) to ApoE-/- mice for 20 weeks reduced the development of atherosclerosis (P<0.05, respectively). Telmisartan decreased lipid deposition (P<0.01) and increased collagen contents (P<0.05) in plaques in ApoE-/- mice. Administration of telmisartan to ApoE-/-AT1aR-/- mice also inhibited the progression of atherosclerosis in aorta (P<0.05) even in mice, which have no AT1aR genetically. Moreover, in these mice, telmisartan decreased macrophage accumulation and lipid deposition, and increased collagen contents in plaques in aortic root (P<0.05, respectively), indicating stabilization of plaques. Telmisartan-treated ApoE-/-AT1aR-/- mice showed lower body weight and higher plasma high-density lipoprotein levels compared with vehicle-treated mice (P<0.05, respectively). Telmisartan lowered systolic and diastolic blood pressure in ApoE-/-AT1aR-/- mice (P<0.01). These results suggest that telmisartan has protective effects on the development of atherosclerosis and metabolic disorders beyond AT1R blockade in ApoE-deficient mice.

The ATP-binding cassette transporter BCRP1/ABCG2 plays a pivotal role in cardiac repair after myocardial infarction via modulation of microvascular endothelial cell survival and function.

OBJECTIVE: To clarify the impact of breast cancer resistance protein 1 (BCRP1)/ATP-binding cassette transporter subfamily G member 2 (ABCG2) expression on cardiac repair after myocardial infarction (MI). METHODS AND RESULTS: The ATP-binding cassette transporter BCRP1/ABCG2 is expressed in various organs, including the heart, and may regulate several tissue defense mechanisms. BCRP1/ABCG2 was mainly expressed in endothelial cells of microvessels in the heart. MI was induced in 8- to 12-week-old wild-type (WT) and Bcrp1/Abcg2 knockout (KO) mice by ligating the left anterior descending artery. At 28 days after MI, the survival rate was significantly lower in KO mice than in WT mice because of cardiac rupture. Echocardiographic, hemodynamic, and histological assessments showed that ventricular remodeling was more deteriorated in KO than in WT mice. Capillary, myofibroblast, and macrophage densities in the peri-infarction area at 5 days after MI were significantly reduced in KO compared with WT mice. In vitro experiments demonstrated that inhibition of BCRP1/ABCG2 resulted in accumulation of intracellular protoporphyrin IX and impaired survival of microvascular endothelial cells under oxidative stress. Moreover, BCRP1/ABCG2 inhibition impaired migration and tube formation of endothelial cells. CONCLUSIONS: BCRP1/ABCG2 plays a pivotal role in cardiac repair after MI via modulation of microvascular endothelial cell survival and function.

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.

Fluvastatin accelerates re-endothelialization impaired by local sirolimus treatment.

Sirolimus-eluting stent reduces restenosis after percutaneous coronary intervention. However, accumulating evidence suggests that sirolimus potentially affects re-endothelialization, leading to late thrombosis. Statins have protective effects on endothelium. Recently, statins are reported to increase the number of circulating endothelial progenitor cells (EPCs) and accelerate re-endothelialization after vascular injury. Here, we tested the hypothesis that fluvastatin has beneficial effect on re-endothelialization after local sirolimus treatment. We performed wire-mediated vascular injury to both sides of femoral arteries of wild-type mice and bone marrow chimeric mice. Either sirolimus (100 microg) or DMSO was administered locally to the perivascular area of the injured arteries. All mice received either fluvastatin (5 mg/kg/day) or vehicle by gavage starting at one week before the surgery until sacrifice. At 4 weeks after the surgery, re-endothelialization of the sirolimus-treated artery was significantly less than that of DMSO-treated one in the vehicle-treated mice as determined by the percentage of CD31-positive area (P<0.05). Systemic administration of fluvastatin accelerated the re-endothelialization in the sirolimus-treated artery to the similar degree of that in the DMSO-treated artery (P=NS). Contribution of bone marrow-derived cells to re-endothelialization was seldom observed in bone marrow chimeric mice regardless of fluvastatin administration. Fluvastatin significantly ameliorated proliferation (2.5-folds) and migration activities (2.3-folds) of mature endothelial cells impaired by sirolimus treatment (P<0.05, respectively). Fluvastatin increased endothelial nitric oxide synthase expression and decreased plasminogen activator inhibitor-1 expression in mature endothelial cell in the presence of sirolimus (P<0.05, respectively). Our findings suggest that fluvastatin has protective effects against impaired re-endothelialization after sirolimus treatment.

Rosuvastatin prevents endothelial cell death and reduces atherosclerotic lesion formation in ApoE-deficient mice.

Accumulating evidence suggests that statins have beneficial effects which are independent of their lipid-lowering actions, on vascular cells. Here, we investigated whether the HMG-CoA reductase inhibitor rosuvastatin can inhibit atherosclerotic lesion development with favorable effects on endothelial cells in ApoE-deficient mice. Rosuvastatin rapidly phosphorylated Akt and endothelial nitric oxide synthase (eNOS) in human endothelial cells. Endothelial cell death induced by serum starvation was significantly inhibited by rosuvastatin (percent cell death; 45.9+/-2.4% vs. 37.3+/-1.1%, p<0.05). Eight-week-old ApoE-deficient mice were orally administered vehicle or rosuvastatin at a dose of 20mg/kg/day for 24 weeks. There was no significant difference in cholesterol profile. Rosuvastatin preserved endothelial lining at the aortic root (CD31-positive luminal side; 63.8+/-2.8% vs. 81.7+/-3.9%, p<0.05). En face Sudan IV staining of aorta revealed that rosuvastatin significantly decreased the atherosclerotic area (21.9+/-2.9% vs. 11.9+/-1.9%, p<0.05). Lipid deposition at the atherosclerotic area was also suppressed by rosuvastatin with more stabilized morphologic features as determined by oil red O staining (3.4+/-0.4% vs. 1.7+/-0.4%, p<0.05). Our findings indicate that rosuvastatin protects endothelial cells from death with phosphorylation of Akt and eNOS. These effects may contribute, at least in part, to the anti-atherosclerotic effects of rosuvastatin.

Hic-5, an adaptor protein expressed in vascular smooth muscle cells, modulates the arterial response to injury in vivo.

Focal adhesion components are targets for biochemical and mechanical stimuli that evoke crucial injury. Hic-5 (hydrogen peroxide-inducible clone 5) is a multidomain adaptor protein which is implicated in the regulation of integrin signaling in focal adhesion. The aim of this research was to test the hypothesis that Hic-5, a focal adhesion LIM protein expressed in smooth muscle cells, is involved in dynamic processes by pathological stimuli in the vessel wall. Here, we describe the analysis of the function of Hic-5 using a mouse model of vascular injury that may mimic balloon angioplasty. At 4 days after vascular injury, marked down-regulation of the Hic-5 expression was observed in the smooth muscle layer, and local delivery of the Hic-5 using adenovirus vectors repressed injury-induced neointimal expansion. In addition, Hic-5 reduced cells migration into three-dimensional collagen gels, and the forced expression of Hic-5 in cells embedded in the collagen gel matrix repressed the expression of uPA that participates in smooth muscle cell migration. These results suggest that Hic-5 modulates cellular responses to pathological stimuli in the vessel wall.

The effects of HMG-CoA reductase inhibitor on vascular progenitor cells.

Circulating bone marrow-derived vascular progenitor cells contribute to angiogenesis, atherosclerosis, and the response to vascular injury. These vascular progenitor cells consist of two cell groups, endothelial progenitor cells (EPCs) and smooth muscle progenitor cells (SMPCs). Although HMG-CoA reductase inhibitors (statins) have been reported to inhibit atherosclerosis partially by increased EPCs, the effects of statins on SMPCs are unclear. Therefore, we investigated the relationship between EPCs and SMPCs and whether pravastatin has atheroprotective effects on SMPCs. Peripheral mononuclear cells (MNCs) were isolated and cultured on fibronectin-coated dishes in SMPC medium. MNCs were stained with acetylated low density lipoprotein and lectin, or alpha-smooth muscle actin, and cell numbers were counted. mRNA expression and vascular endothelial growth factor (VEGF) protein synthesis of MNCs were evaluated. Pravastatin significantly increased the number of EPC and decreased the number of SMPC. mRNA expression of VEGF, endothelial nitric oxide synthase, VEGF receptor-2 (KDR), and Akt were up-regulated, and VEGF secretion was increased by pravastatin. The present study demonstrated that pravastatin has promotive effects on the differentiation from MNCs to EPC cells, while inhibitory effects to SMPC cells. Our findings suggest a previously unreported mechanism of the effect of statin therapy on vascular progenitor cells.

Effects of erythropoietin on cardiac remodeling after myocardial infarction.

Erythropoietin (EPO) has been suggested to have a cardioprotective effect against ischemia. The purpose of this study was to examine the effects of EPO on cardiac remodeling after myocardial infarction (MI). MI was induced by ligation of the coronary artery in Wistar rats. The rats with MI were randomly divided into untreated MI and two EPO-treated MI groups. EPO was administered subcutaneously by injection once a day for 4 days after MI at 5000 U/kg or 3 times a week for 4 weeks at 1000 U/kg. Five days after MI, EPO prevented the increase in activated caspase 3, matrix metalloproteinase-2, and transcriptional activation of activator protein-1 in non-infarcted myocardium. Four weeks after MI, left ventricular weight, left ventricular end-diastolic pressure, and left ventricular dimension were increased, and ejection fraction and E wave deceleration time were decreased. EPO significantly attenuated this ventricular remodeling and systolic and diastolic dysfunction. In addition, EPO significantly attenuated the interstitial fibrosis and remodeling-related gene expression in non-infarcted myocardium. Furthermore, EPO significantly enhanced angiogenesis and reduced apoptotic cell death in peri-infarcted myocardium. In conclusion, when administered after MI, EPO prevents cardiac remodeling and improves ventricular function with enhanced angiogenesis and reduced apoptosis.