Macrophage skewing by Phd2 haplodeficiency prevents ischaemia by inducing arteriogenesis.

PHD2 serves as an oxygen sensor that rescues blood supply by regulating vessel formation and shape in case of oxygen shortage. However, it is unknown whether PHD2 can influence arteriogenesis. Here we studied the role of PHD2 in collateral artery growth by using hindlimb ischaemia as a model, a process that compensates for the lack of blood flow in case of major arterial occlusion. We show that Phd2 (also known as Egln1) haplodeficient (Phd2(+/-)) mice displayed preformed collateral arteries that preserved limb perfusion and prevented tissue necrosis in ischaemia. Improved arteriogenesis in Phd2(+/-) mice was due to an expansion of tissue-resident, M2-like macrophages and their increased release of arteriogenic factors, leading to enhanced smooth muscle cell (SMC) recruitment and growth. Both chronic and acute deletion of one Phd2 allele in macrophages was sufficient to skew their polarization towards a pro-arteriogenic phenotype. Mechanistically, collateral vessel preconditioning relied on the activation of canonical NF-κB pathway in Phd2(+/-) macrophages. These results unravel how PHD2 regulates arteriogenesis and artery homeostasis by controlling a specific differentiation state in macrophages and suggest new treatment options for ischaemic disorders.

Sex differences in clinical characteristics and long-term outcome in acute decompensated heart failure patients with preserved and reduced ejection fraction.

In patients with acute decompensated heart failure (ADHF), sex differences considering clinical and pathophysiologic features are not fully understood. We investigated sex differences in left ventricular (LV) ejection fraction (LVEF), plasma B-type natriuretic peptide (BNP) levels, and prognostic factors in patients with ADHF in Japan. We studied 748 consecutive ADHF patients of 821 patients registered in the ADHF registry between January 2007 and December 2014. Patients were divided into four groups based on sex and LVEF [reduced (ejection fraction, or EF, <50%, heart failure with reduced EF, or HFrEF) or preserved (EF ≥50%, heart failure with preserved LVEF, or HFpEF)]. The primary endpoint was the combination of cardiovascular death and heart failure (HF) admission. The present study consisted of 311 female patients (50% HFrEF, 50% HFpEF) and 437 male patients (63% HFrEF, 37% HFpEF). There was significant difference between sexes in the LVEF distribution profile. The ratio of HFpEF patients was significantly higher in female patients than in male patients (P= 0.0004). Although there were no significant sex differences in median plasma BNP levels, the prognostic value of BNP levels was different between sexes. Kaplan-Meier analysis revealed that the high BNP group had worse prognosis than the low BNP group in male but not in female patients. In multivariate analysis, log transformed BNP at discharge predicted cardiovascular events in male but not in female HF patients (female, hazard ratio: 1.169; 95% confidence interval: 0.981-1.399;P= 0.0806; male, hazard ratio: 1.289; 95% confidence interval: 1.120-1.481;P= 0.0004). In patients with ADHF, the distribution of LV function and the prognostic significance of plasma BNP levels for long-term outcome were different between the sexes.

Placental Growth Factor as a Predictor of Cardiovascular Events in Patients with CKD from the NARA-CKD Study.

Placental growth factor (PlGF) contributes to atherogenesis through vascular inflammation and plaque destabilization. High levels of PlGF may be associated with mortality and cardiovascular disease, but the relationship between PlGF level and adverse outcomes in patients with CKD is unclear. We conducted a prospective cohort study of 1351 consecutive participants with CKD enrolled in the Novel Assessment of Risk management for Atherosclerotic diseases in CKD (NARA-CKD) study between April 1, 2004, and December 31, 2011. During a median follow-up of 3 years, 199 participants died and 383 had cardiovascular events, defined as atherosclerotic disease or heart failure requiring hospitalization. In adjusted analyses, mortality and cardiovascular risk increased in each successive quartile of serum PlGF level; hazard ratios (HRs) (95% confidence intervals [95% CIs]) for mortality and cardiovascular risk, respectively, were 1.59 (0.83 to 3.16) and 1.55 (0.92 to 2.66) for the second quartile, 2.97 (1.67 to 5.59) and 3.39 (2.20 to 5.41) for the third quartile, and 3.87 (2.24 to 7.08) and 8.42 (5.54 to 13.3) for the fourth quartile. The composite end point of mortality and cardiovascular events occurred during the study period in 76.4% of patients in both the highest PlGF quartile (≥19.6 pg/ml) and the lowest eGFR tertile (<30 ml/min per 1.73 m(2)). The association between PlGF and mortality or cardiovascular events was not attenuated when participants were stratified by age, sex, traditional risk factors, and eGFR. These data suggest elevated PlGF is an independent risk factor for all-cause mortality and cardiovascular events in patients with CKD.

Prognostic Impact of Placental Growth Factor on Mortality and Cardiovascular Events in Dialysis Patients.

BACKGROUND: Placental growth factor (PlGF), a member of the vascular endothelial growth factor (VEGF) family, has recently emerged as a predictor of survival and cardiovascular risk. Along with others, we have shown an independent association between PlGF and cardiovascular events in CKD patients, but not much is known about patients receiving dialysis. METHODS: We studied 205 dialysis patients undergoing cardiac catheterization at the Nara Medical University between April 1, 2004, and December 31, 2012. Serum levels of PlGF and VEGF were measured with ELISA in all the patients. RESULTS: During a median follow-up of 20 months, 121 participants died from any cause or experienced a cardiovascular event. In the fully adjusted analysis, having an above-median PlGF or VEGF level was associated with a hazards ratio for adverse outcomes of 2.55 (1.72-3.83) and 1.39 (0.95-2.04), respectively. Using a multimarker strategy in a model with age, serum albumin, history of coronary artery disease, brain natriuretic peptide and PlGF, patients with 2, 3 and 4 positive markers had a 3.82-, 5.77- and 6.59-fold higher risk of mortality or a cardiovascular event, respectively, compared to those with no positive markers. The model with PlGF had a significantly higher c-statistic, integrated discrimination improvement index and category-free net reclassification improvement index than the model without PlGF. CONCLUSION: PlGF is independently associated with mortality and cardiovascular events, but the association between VEGF and adverse events was attenuated with covariate adjustment. The addition of PlGF to models with established clinical predictors provides additional useful prognostic information in patients receiving dialysis.

Major non-cardiac surgery is a risk factor for rapid hemodynamic progression of non-rheumatic aortic stenosis.

BACKGROUND: Inflammatory processes are suggested to play a pathogenic role in the development and progression of non-rheumatic aortic stenosis (AS). Major surgery causes an inflammatory reaction. With the increasing prevalence of non-rheumatic AS, the number of affected patients undergoing major surgery increases. We hypothesized that major non-cardiac surgery (MNCS) could accelerate the progression of non-rheumatic AS. METHODS AND RESULTS: We enrolled 218 consecutive patients with non-rheumatic AS who underwent transthoracic echocardiography (TTE) at least twice more than 6 months apart. Study patients were divided into the MNCS group and the non-MNCS group. The MNCS group consisted of patients who underwent MNCS during the TTE follow-up interval. At baseline, peak pressure gradient across the aortic valve (AVG) was similar between the groups. Also baseline clinical characteristics and TTE follow-up interval were similar. The annual rate of peak AVG increase was much higher in the MNCS group than in the non-MNCS group. The proportion of patients with rapid hemodynamic progression was much higher in the MNCS group than in the non-MNCS group. Multiple logistic regression analysis showed that MNCS was an independent predictor of rapid hemodynamic progression of non-rheumatic AS. CONCLUSIONS: The present study indicates for the first time that MNCS is associated with the rapid progression of non-rheumatic AS.

Left Ventricular Ejection Fraction (EF) of 55% as Cutoff for Late Transition From Heart Failure (HF) With Preserved EF to HF With Mildly Reduced EF.

BACKGROUND: Heart failure (HF) with preserved (HFpEF) left ventricular ejection fraction (LVEF) is a syndrome with complex pathophysiology. Little is known about changes in LVEF that occur over time in HFpEF patients. A fundamental clinical question about HFpEF is whether HFpEF is an early manifestation of HF with reduced LVEF (HFrEF). If so, which patients with HFpEF are likely to show a decline in LVEF to less than 50%? The aim of the present study was to examine longitudinal changes in LVEF in patients with HFpEF. METHODS AND RESULTS: Among 279 consecutive HFpEF patients admitted as emergencies, we examined 100 who underwent echocardiography at least 1 year after discharge. EF >50% was used as the definition of HFpEF. During a mean duration from hospitalization to follow-up echocardiography of 31.5 months, 11% of patients had LVEF ≤50% (mildly reduced LVEF), known as mildly reduced (HFmrEF). The utility of LVEF during hospitalization to predict HFmrEF was assessed with receiver-operating characteristic curve analysis. A cutoff value of 55% had sensitivity of 90.9% and specificity of 97.7%. Logistic regression analysis indicated that LVEF ≤55% and ischemic etiology were strong predictors of progression from HFpEF to HFmrEF (odds ratio [OR] 435, 95% confidence interval [CI] 52.65-10,614, P<0.0001 and OR 10.9, 95% CI 2.60-74.80, P=0.0007, respectively). CONCLUSIONS: The present study suggests that HFpEF patients with LVEF ≤55% may progress to HFmrEF in the future.

Plasma renin activity is a strong and independent prognostic indicator in patients with acute decompensated heart failure treated with renin-angiotensin system inhibitors.

BACKGROUND: The renin-angiotensin system (RAS) is activated in heart failure (HF) as a compensatory mechanism, being related to cardiac remodeling and poor prognosis. Although RAS inhibitors are used as first-line drugs for HF, plasma renin activity (PRA) is upregulated by RAS inhibitors via a negative feedback mechanism. The clinical significance of PRA during RAS inhibitor therapy is poorly understood in acute decompensated HF (ADHF). Therefore we examined the impact of PRA in HF patients already receiving RAS inhibitors. METHODS AND RESULTS: Of 611 consecutive patients with ADHF and emergency admission to hospital, we studied the impact of PRA on the prognosis of ADHF in 293 patients already receiving RAS inhibitors before admission. The patients were divided into 2 groups according to median PRA (≥ vs. <3.4 ng·ml(-1)·h(-1)). During a mean follow-up of 29.0 months, there were 124 deaths from all causes. Kaplan-Meier analysis showed that all-cause and cardiovascular mortality were significantly higher in patients with high PRA than low PRA (log-rank P=0.0002 and P<0.0001, respectively). Log PRA was an independent predictor of all-cause and cardiovascular death (HR, 1.194; 95% CI: 1.378-2.678, P<0.0001; and HR, 2.559; 95% CI: 1.610-4.144, P<0.0001, respectively). CONCLUSIONS: PRA was associated with an increased risk of all-cause and cardiovascular mortality in ADHF patients already receiving RAS inhibitors, suggesting that PRA would be a useful biomarker during ADHF treatment.

Echocardiographic characteristics of patients with acute heart failure requiring tolvaptan: a retrospective study.

BACKGROUND: No study has investigated the admission echocardiographic characteristics of acute heart failure (AHF) patients who are resistant to conventional diuretics and require tolvaptan. METHODS: We retrospectively analyzed the echocardiographic characteristics of AHF patients who were resistant to conventional diuretics and took tolvaptan (tolvaptan group: 26 patients), and compared them to those who were sensitive to conventional diuretics (conventional group: 180 patients). RESULTS: The tolvaptan group had a higher left atrial volume index (96.0 ± 85.0 mL/m2 vs. 45.8 ± 25.9 mL/m2, p < 0.0001), maximum inferior vena cava diameter (20.7 ± 6.9 mm vs. 18.1 ± 4.2 mm, p < 0.01), and higher tricuspid regurgitation grade (1.1 ± 0.8 vs. 0.8 ± 0.6, p < 0.05) than the conventional group. However, the left ventricular ejection fraction and end diastolic diameter were similar between the groups. Responders of tolvaptan had no significant echocardiographic differences compared to the non-responders. CONCLUSIONS: The admission echocardiographic characteristics of AHF patients requiring tolvaptan included a larger left atrium, inferior vena cava, and more severe tricuspid regurgitation. Echocardiography may provide useful information for the early and appropriate initiation of tolvaptan.

Suppressed soluble Fms-like tyrosine kinase-1 production aggravates atherosclerosis in chronic kidney disease.

Patients with chronic kidney disease (CKD) die of cardiovascular diseases for unknown reasons. Blood vessel formation in plaques and its relationship with plaque stability could be involved with signaling through the Flt-1 receptor and its ligands, vascular endothelial growth factor, and the closely related placental growth factor (PlGF). Flt-1 also exists as a circulating regulatory splice variant short-inhibitory form (sFlt-1) that serves as a decoy receptor, thereby inactivating PlGF. Heparin releases sFlt-1 by displacing the sFlt-1 heparin-binding site from heparin sulfate proteoglycans. Heparin could provide diagnostic inference or could also induce an antiangiogenic state. In the present study, postheparin sFlt-1 levels were lower in CKD patients than in control subjects. More importantly, sFlt-1 levels were inversely related to atherosclerosis in CKD patients, and this correlation was more robust after heparin injection, as verified by subsequent cardiovascular events. Knockout of apolipoprotein E (ApoE) and/or sFlt-1 showed that the absence of sFlt-1 worsened atherogenesis in ApoE-deficient mice. Thus, the relationship between atherosclerosis and PlGF signaling, as regulated by sFlt-1, underscores the underappreciated role of heparin in sFlt-1 release. These clinical and experimental data suggest that novel avenues into CKD-dependent atherosclerosis and its detection are warranted.

Noncardiovascular death, especially infection, is a significant cause of death in elderly patients with acutely decompensated heart failure.

BACKGROUND: Despite marked improvements in treatment strategies for heart failure (HF), the mortality rate of elderly patients with HF is still high. Detailed causes of death have not been fully understood. METHODS AND RESULTS: We studied 459 consecutive patients with acute decompensated HF (ADHF) emergently admitted to our hospital from 2007 to 2011. Patients were divided into 2 groups: <75 years old (younger group; n = 225) and ≥75 years old (elderly group; n = 234). All-cause death, cardiovascular death, and noncardiovascular death were assessed as adverse outcomes. Compared with the younger group, the elderly group was characterized by a higher proportion of women and hypertensive patients and higher left ventricular ejection fraction. During a mean follow-up of 20.7 months, a total of 174 patients (37.9%) died. All-cause death was significantly higher in the elderly group than in the younger group (46.6% vs 28.9%; P < .0001), and this difference was caused by an increase in noncardiovascular deaths (20.9% vs 9.3%; P < .001), especially deaths due to infection (10.7% vs 4.0%; P < .01). Cardiovascular deaths did not differ between the 2 groups. CONCLUSIONS: Noncardiovascular deaths, most of which were caused by infection, were frequent among elderly patients with ADHF.

High mean corpuscular volume is a new indicator of prognosis in acute decompensated heart failure.

BACKGROUND: Accumulating evidence suggests that hematopoiesis, especially erythropoiesis, is disturbed in heart failure (HF) for many reasons. Low hemoglobin and red blood cell distribution width have emerged as prognostic indicators of HF independent of classic predictors. The prognostic implication of mean corpuscular volume (MCV) in HF, however, is unknown. In this context, we investigated the relationship between MCV and prognosis of acute decompensated HF (ADHF). METHODS AND RESULTS: This retrospective cohort study consisted of 458 consecutive patients with ADHF who had emergency admission to hospital. Patients were divided into 2 groups: MCV ≤100fl (non-macrocytic group, n=400); and MCV >100fl (macrocytic group, n=58). The relationship between MCV and all-cause death was tested using Cox proportional hazard models, adjusting for other predictors. Mean patient age was 72.4 years and mean MCV was 93.0±7.1fl. Hemoglobin was significantly lower in the macrocytic group than the non-macrocytic group. During the mean follow-up of 20.8 months, a total of 173 deaths (37.9%) occurred. Kaplan-Meier analysis showed that all-cause death was significantly higher in the macrocytic group (log-rank P<0.0001). Cox proportional hazards analysis indicated that macrocytosis was an independent predictor of all-cause death (hazard ratio, 2.288; 95% confidence interval: 1.390-3.643; P=0.0015) after adjustment in the multivariate model. CONCLUSIONS: It is proposed for the first time that MCV is an independent predictor of all-cause death in patients with ADHF.

Primary cardiac lymphoma: echocardiography and F-18-fluorodeoxyglucose positron emission tomography in selection of a biopsy site.

A 63-year-old man was referred to our hospital because of a cardiac tumor. Transthoracic echocardiography revealed a rough, mobile tumor in the dilated right atrium, and transesophageal echocardiography showed that the tumor consisted of small, botryoidal masses. Catheter-based biopsy carried a high risk of embolism. Therefore, we used F-18-fluorodeoxyglucose positron emission tomography (FDG-PET), which revealed an abnormal accumulation in the right cervical lymph nodes, as well as in the heart. We safely performed biopsy of the lymph nodes and diagnosed the patient with primary cardiac lymphoma. We concluded that echocardiography and FDG-PET are useful for selecting an appropriate biopsy site in primary cardiac lymphoma.

Thin-cap fibroatheroma and microchannel findings in optical coherence tomography correlate with subsequent progression of coronary atheromatous plaques.

AIMS: Morphological characteristics of non-significant coronary plaques (NSCPs) that develop rapid progression have not been fully elucidated. The aim of this study was to clarify the morphological characteristics of NSCPs in patients with coronary artery disease (CAD) using intravascular optical coherence tomography (OCT). METHODS AND RESULTS: Fifty-three consecutive CAD patients undergoing percutaneous coronary intervention were enrolled and 69 NSCPs (per cent diameter stenosis <50%) were identified on baseline angiogram. Baseline characteristics of NSCPs were evaluated by OCT, and patients were followed-up prospectively. At the second coronary angiography, the baseline OCT characteristics and plaque progression were correlated. During the 7-month follow-up period, 13 NSCPs showed angiographic progression and 56 NSCPs did not. Baseline minimum lumen diameter and diametric stenosis were similar between NSCPs with and without progression. Compared with NSCPs without progression, those with progression showed a significantly higher incidence of intimal laceration (61.5 vs. 8.9%, P < 0.01), microchannel (76.9 vs. 14.3%, P < 0.01), lipid pools (100 vs. 60.7%, P = 0.02), thin-cap fibroatheroma (TCFA) (76.9 vs. 14.3%, P < 0.01), macrophage images (61.5 vs. 14.3%, P < 0.01), and intraluminal thrombi (30.8 vs. 1.8%, P < 0.01). Univariate regression analysis showed that TCFA and microchannel images showed high correlation with subsequent luminal progression [odds ratio (OR): 20.0, P < 0.01 and OR: 20.0, P < 0.01, respectively]. CONCLUSION: Optical coherence tomography-based complex characteristics of TCFA and microchannel were the potential predictors of subsequent progression of NSCPs in patients with CAD.

Non-contact mapping system accurately localizes right-sided accessory pathways in type B Wolff-Parkinson-White syndrome.

AIMS: Ablation of right-sided accessory pathways (APs) is sometimes challenging because several anatomical features of the tricuspid annulus (TA) and surrounding structures differ from those of the mitral annulus. This study investigated the electrophysiological characteristics and efficacy of a non-contact mapping (NCM) system for catheter ablation of right-sided APs. METHODS AND RESULTS: We examined nine APs in six consecutive patients who underwent catheter ablation of right-sided APs with NCM. In Case 6, we compared NCM with contact activation mapping. Three of six patients had two APs, and one of these had previously failed ablation. We observed atrial activation during sinus rhythm or atrial pacing using a multiple-electrode array (MEA) deployed in the right atrium near the TA. Non-contact mapping identified the AP location as a peri-TA breakout point that appeared prior to or simultaneously with the delta wave onset in all APs. In Case 6 we confirmed that the peri-TA breakout identified by NCM corresponded to the earliest ventricular activation identified by contact mapping. We successfully ablated nine APs by radiofrequency (RF) energy application to the breakout sites, while one AP located just above the pole of the MEA required additional conventionally guided mapping and ablation. The mean RF duration was 189.8 ± 119.0 s. After 33.2 ± 9.4 months of follow-up, one para-hisian AP and one right lateral AP recurred, but these were successfully ablated in a second procedure using NCM. CONCLUSION: Non-contact mapping was able to identify the location of right-sided APs accurately and quickly.

Intensive lipid-lowering therapy with rosuvastatin stabilizes lipid-rich coronary plaques. -Evaluation using dual-source computed tomography.-.

BACKGROUND: Clinical studies using invasive modalities have reported that statin therapy stabilizes coronary plaque vulnerability. The serial changes of lipid-rich coronary plaques (LRCPs) during rosuvastatin treatment were evaluated non-invasively in patients with acute coronary syndrome (ACS) using dual-source computed tomography (DSCT). METHODS AND RESULTS: A total of 11 consecutive ACS patients, and 13 LRCPs were serially evaluated on DSCT before and 24 weeks after rosuvastatin treatment. Compared with the baseline, there was no change in post-treatment minimal lumen diameter, lumen volume, or longitudinal length of LRCPs. By contrast, the ratio of lipid core volume to plaque volume significantly decreased from 48.0 ± 9.9% to 43.7 ± 10.6% (P=0.04), and plaque volume decreased from 144.5 ± 85.5 mm³ to 119.8 ± 78.0 mm³ (P=0.07). The remodeling index of target LRCPs significantly decreased from 1.16 ± 0.10 to 1.06 ± 0.12 (P=0.02). Percent reduction of plaque volume was significantly greater in patients with a lower ratio of low-density lipoprotein to high-density lipoprotein (L/H ratio ≤ 1.5) at follow-up than patients with higher L/H ratio (>1.5; median -31.7% vs. -6.8%, P=0.03). CONCLUSIONS: Rosuvastatin therapy reduced the volume of lipid cores and LRCPs and increased the CT attenuation value of LRCPs. DSCT is an effective modality for the non-invasive evaluation of LRCPs in patients with ACS. ).

Reduction of circulating soluble fms-like tyrosine kinase-1 plays a significant role in renal dysfunction-associated aggravation of atherosclerosis.

BACKGROUND: Renal dysfunction is commonly accompanied by a worsening of atherosclerosis; however, the underlying molecular mechanism is not fully understood. We examined the role played by soluble fms-like tyrosine kinase-1 (sFlt-1), an endogenous antagonist of the proatherogenic cytokine placental growth factor (PlGF), in the worsening of atherosclerosis in patients with renal dysfunction and in an animal model of renal failure. METHODS AND RESULTS: In this study, 329 patients who received cardiac catheterization and 76 patients who underwent renal biopsy were enrolled. Both plasma sFlt-1 levels and renal sFlt-1 mRNA expression were positively correlated with estimated glomerular filtration rate (P<0.01). The PlGF/sFlt-1 ratio was negatively correlated with estimated glomerular filtration rate (P<0.01), whereas plasma PlGF levels were not affected by it. The PlGF/sFlt-1 ratio was significantly higher in patients with multivessel coronary artery disease than in patients with single-vessel or no coronary artery disease. The reduction of circulating sFlt-1 and renal sFlt-1 mRNA levels was confirmed in five-sixths (5/6)-nephrectomized apolipoprotein E-deficient mice that developed experimental renal dysfunction. Atherosclerotic plaque area and macrophage infiltration into the plaque were significantly higher in 5/6-nephrectomized apolipoprotein E-deficient mice than in control mice, but replacement therapy with recombinant sFlt-1 significantly reduced both plaque formation and macrophage infiltration. CONCLUSIONS: The present study demonstrates that a reduction in the circulating levels of sFlt-1 is associated with the worsening of atherosclerosis that accompanies renal dysfunction.

Human placental ectonucleoside triphosphate diphosphohydrolase gene transfer via gelatin-coated stents prevents in-stent thrombosis.

BACKGROUND: In-stent thrombosis is mainly triggered by adenosine diphosphate (ADP)-dependent platelet aggregation after percutaneous coronary stent implantation. Ectonucleoside triphosphate diphosphohydrolase (E-NTPDase) rapidly hydrolyzes ADP to adenosine monophosphate, inhibiting platelet aggregation. We tested the hypothesis that local delivery of human placental E-NTPDase (pE-NTPDase) gene into injured arteries via gene-eluting stent could prevent subacute in-stent thrombosis. METHODS AND RESULTS: We generated gene-eluting stents by coating bare metal stents with cationic gelatin hydrogel containing pE-NTPDase cDNA (pE-NTPDase stent), and implanted the stents into rabbit femoral arteries (FA) prone to production of platelet-rich thrombi due to repeated balloon injury at 4-week intervals. After the second injury, E-NTPDase gene expression was severely decreased; however, the implantation of pE-NTPDase stent increased E-NTPDase mRNA levels and NTPDase activity to higher level than normal FA. The FAs with pE-NTPDase stents maintained patency in all rabbits (P<0.01), whereas the stent-implanted FAs without pE-NTPDase gene showed low patency rates (17% to 25%). The occlusive platelet-rich thrombi, excessive neointimal growth, and infiltration of macrophages were inhibited in stent implanted FA with pE-NTPDase gene, but not without pE-NTPDase gene. CONCLUSIONS: Human pE-NTPDase gene transfer via cationic gelatin-coated stents inhibited subacute in-stent thrombosis and suppressed neointimal hyperplasia and inflammation without antiplatelet drugs.

Novel application of black-blood echo-planar imaging to the assessment of myocardial infarction.

The purpose of this study was to clarify the characteristics of black-blood echo-planar imaging (BB-EPI) in the assessment of infarct-related myocardial edema (IRME), compared with T2-weighted imaging (T2WI). Thirteen acute myocardial infarction (MI) patients after reperfusion and 11 old MI patients underwent BB-EPI and T2WI, excluding those with posterior MI. In acute MI patients, signal intensity ratio (SI ratio) of edema to normal myocardium was measured. Black-blood echo-planar imaging revealed hyperintensity in the same region identified as IRME on T2WI in all acute MI patients, and SI ratio was significantly higher in BB-EPI (2.66 +/- 1.58) than in T2WI (1.44 +/- 0.22) (P < 0.05). However, BB-EPI showed hyperintensity in posterior wall, where there is no clinical evidence of acute MI, in 2 out of 13 acute MI patients. Both T2WI and BB-EPI detected no IRME in known old infarct area of all old MI patients, but BB-EPI showed hyperintensity in the posterior wall of 4 out of 11 old MI patients. Black-blood echo-planar imaging can depict IRME with sufficient suppression of background and blood flow signals, and with excellent edema-to-normal myocardium contrast resolution. However, BB-EPI sometimes shows an inconsistent signal area with T2WI specifically in posterior wall. The wide practical use of BB-EPI requires the solution to this serious problem.

Long-term follow-up of neointimal coverage of sirolimus-eluting stents--evaluation with optical coherence tomography.

BACKGROUND: Late stent thrombosis related to delayed neointimal growth is a major concern after drug-eluting stent (DES) implantation. The time course of neointimal growth and risk factors of uncovered stent struts after sirolimus-eluting stent (SES) was studied using optical coherence tomography (OCT). METHODS AND RESULTS: The 60 patients were enrolled and classified into G1 (follow-up period <9 months, n=27), G2 (9-24 months, n=18), and G3 (>25 months, n=15). The time elapsed since SES implantation was associated with a significant increase in mean neointimal area and neointimal thickness, and also with a significant decrease in the number of uncovered stent struts (G1: 14.8%, G2: 11.7%, and G3: 4.1%, P<0.001). However, only 17.6% of implanted SES was completely covered by neointima, even in the G3 period. Small-diameter SES, complex coronary lesions with lipid and calcium content adjacent to stent struts, and diabetes predicted delayed neointimal coverage of SES struts in G1. CONCLUSIONS: Neointima inside SES progressively increases after the routine follow-up period, but only a few SES were completely covered at 3 years after implantation. OCT is a useful modality for assessing neointimal formation after SES implantation, and may give important information about the strategy of antiplatelet therapy after DES implantation.

Treatment with recombinant placental growth factor (PlGF) enhances both angiogenesis and arteriogenesis and improves survival after myocardial infarction.

BACKGROUND: Placental growth factor (PlGF), a homolog of vascular endothelial growth factor, is reported to stimulate angiogenesis and arteriogenesis in pathological conditions. It was recently demonstrated that PlGF is rapidly produced in myocardial tissue during acute myocardial infarction (MI). However, the effects of exogenous PlGF administration on the healing process after MI are not fully understood. The purpose of the present study was to examine whether PlGF treatment has therapeutic potential in MI. METHODS AND RESULTS: Recombinant human PlGF (rhPlGF: 10 microg) was administered continuously for 3 days in a mouse model of acute MI. rhPlGF treatment significantly improved survival rate after MI and preserved cardiac function relative to control mice. The numbers of CD31-positive cells and alpha-smooth muscle actin-positive vessels in the infarct area were significantly increased in the rhPlGF group. Endothelial progenitor cells (Flk-1(+)Sca-1(+) cells) were mobilized by rhPlGF into the peripheral circulation. Furthermore, rhPlGF promoted the recruitment of GFP-labeled bone marrow cells to the infarct area, but only a few of those migrating cells differentiated into endothelial cells. CONCLUSIONS: Exogenous PlGF plays an important role in healing processes by improving cardiac function and stimulating angiogenesis following MI. It can be considered as a new therapeutic molecule.