Suppressed Production of Soluble Fms-Like Tyrosine Kinase-1 Contributes to Myocardial Remodeling and Heart Failure.

Soluble fms-like tyrosine kinase-1 (sFlt-1), an endogenous inhibitor of vascular endothelial growth factor and placental growth factor, is involved in the pathogenesis of cardiovascular disease. However, the significance of sFlt-1 in heart failure has not been fully elucidated. We found that sFlt-1 is decreased in renal failure and serves as a key molecule in atherosclerosis. In this study, we aimed to investigate the role of the decreased sFlt-1 production in heart failure, using sFlt-1 knockout mice. sFlt-1 knockout mice and wild-type mice were subjected to transverse aortic constriction and evaluated after 7 days. The sFlt-1 knockout mice had significantly higher mortality (52% versus 15%; P=0.0002) attributable to heart failure and showed greater cardiac hypertrophy (heart weight to body weight ratio, 8.95±0.45 mg/g in sFlt-1 knockout mice versus 6.60±0.32 mg/g in wild-type mice; P<0.0001) and cardiac dysfunction, which was accompanied by a significant increase in macrophage infiltration and cardiac fibrosis, than wild-type mice after transverse aortic constriction. An anti-placental growth factor-neutralizing antibody prevented pressure overload-induced cardiac hypertrophy, fibrosis, and cardiac dysfunction. Moreover, monocyte chemoattractant protein-1 expression was significantly increased in the hypertrophied hearts of sFlt-1 knockout mice compared with wild-type mice. Monocyte chemoattractant protein-1 inhibition with neutralizing antibody ameliorated maladaptive cardiac remodeling in sFlt-1 knockout mice after transverse aortic constriction. In conclusion, decreased sFlt-1 production plays a key role in the aggravation of cardiac hypertrophy and heart failure through upregulation of monocyte chemoattractant protein-1 expression in pressure-overloaded heart.

Angiogenic Factors and Risks of Technique Failure and Cardiovascular Events in Patients Receiving Peritoneal Dialysis.

BACKGROUND: Placental growth factor (PlGF) is a member of the vascular endothelial growth factor family that acts as a pleiotropic cytokine capable of stimulating angiogenesis and accelerating atherogenesis. Soluble fms-like tyrosine kinase-1 (sFlt-1) antagonizes PlGF action. Higher levels of PlGF and sFlt-1 have been associated with cardiovascular events in patients with chronic kidney disease, yet little is known about their relationship with adverse outcomes in patients on peritoneal dialysis (PD). The aim of this study was to investigate the association of PlGF and sFlt-1 with technique survival and cardiovascular events. METHODS: We measured serum levels of PlGF and plasma levels of sFlt-1 in 40 PD patients at Nara Medical University. RESULTS: PlGF and sFlt-1 levels were significantly correlated with the dialysate-to-plasma ratio of creatinine (r = 0.342, p = 0.04 and r = 0.554, p < 0.001) although PlGF and sFlt-1 levels were not correlated with total creatinine clearance and total Kt/V. Additionally, both PlGF and sFlt-1 levels were significantly higher in patients with high transport membranes compared to those without (p = 0.039 and p < 0.001, respectively). Patients with PlGF levels above the median had lower technique survival and higher incidence of cardiovascular events than patients with levels below the median, with hazard ratios of 11.9 and 7.7, respectively, in univariate Cox regression analysis. However, sFlt-1 levels were not associated with technique survival or cardiovascular events (p = 0.11 and p = 0.10, respectively). CONCLUSION: Elevated PlGF and sFlt-1 are significantly associated with high transport membrane status. PlGF may be a useful predictor of technique survival and cardiovascular events in PD patients.

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.

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.

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.

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.

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.

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.

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.

Worsening of renal function during 1 year after hospital discharge is a strong and independent predictor of all-cause mortality in acute decompensated heart failure.

BACKGROUND: Renal impairment is a common comorbidity and the strongest risk factor for poor prognosis in acute decompensated heart failure (ADHF). In clinical practice, renal function is labile during episodes of ADHF, and often worsens after discharge. The significance of worsening of renal function (WRF) after discharge has not been investigated as extensively as baseline renal function at admission or WRF during hospitalization. METHODS AND RESULTS: Among 611 consecutive patients with ADHF emergently admitted to our hospital, 233 patients with 3 measurements of serum creatinine (SCr) level measurements (on admission, at discharge, and 1 year after discharge) were included in the present study. Patients were divided into 2 groups according to the presence or absence of WRF at 1 year after discharge (1y-WRF), defined as an absolute increase in SCr >0.3 mg/dL (>26.5 µmol/L) plus a ≥25% increase in SCr at 1 year after discharge compared to the SCr value at discharge. All-cause and cardiovascular mortality were assessed as adverse outcomes. During a mean follow-up of 35.4 months, 1y-WRF occurred in 48 of 233 patients. There were 66 deaths from all causes. All-cause and cardiovascular mortality were significantly higher in patients with 1y-WRF (log-rank P<0.0001 and P<0.0001, respectively) according to Kaplan-Meier analysis. In a multivariate Cox proportional hazards model, 1y-WRF was a strong and independent predictor of all-cause and cardiovascular mortality. Hemoglobin and B-type natriuretic peptide at discharge, as well as left ventricular ejection fraction <50%, were independent predictors of 1y-WRF. CONCLUSIONS: In patients with ADHF, 1y-WRF is a strong predictor of all-cause and cardiovascular mortality.

Side branch complication after a single-stent crossover technique: prediction with frequency domain optical coherence tomography.

OBJECTIVES: To identify preprocedural predictors of side branch (SB) complications after coronary bifurcation stent implantation using frequency domain optical coherence tomography (FD-OCT). BACKGROUND: Coronary bifurcation lesions are common but difficult to treat. Longitudinal reconstruction images of FD-OCT have high image quality and less motion artifacts. METHODS: Among 49 patients (age: 69.9 years) who underwent elective coronary stenting, 52 bifurcation lesions without baseline SB stenosis were studied. SB complication was defined as angiographic worsening of SB stenosis (>75%). On the basis of preprocedural FD-OCT imaging, plaque distribution, SB angle, carina tip angle (CT angle), and length between proximal branching point to carina tip (BP-CT length) were evaluated. RESULTS: SB complication was observed in 22 lesions. The eccentric plaque distribution oriented toward the opposite side of SB at the CT was significantly more frequent in lesions with SB complication compared with those without (77.3 vs. 16.7%, P<0.01). CT angle and BP-CT length were significantly smaller in lesions with SB complication compared with those without [29.5° (interquartile range (IQR) 22.3-44.3°) vs. 65.0° (IQR 42.5-90.0°)], P<0.001; 1.20 mm (IQR 0.70-1.73 mm) vs. 2.25 mm (IQR 1.78-3.20 mm), P<0.001, respectively]. The receiver-operating characteristic curve indicated a CT angle less than 50° (area under the curve=0.81, sensitivity 86%, specificity 70%) and BP-CT length less than 1.70 mm (area under the curve=0.84, sensitivity 77%, specificity 77%) as the best cutoff values for predicting the SB complication after main vessel stent implantation. CONCLUSION: This FD-OCT study showed that narrower CT angle and shorter BP-CT length were the independent predictors for SB complications after bifurcation stenting.

Colocalization of thin-cap fibroatheroma and spotty calcification is a powerful predictor of procedure-related myocardial injury after elective coronary stent implantation.

OBJECTIVES: Percutaneous coronary intervention (PCI)-related cardiac enzyme elevation is an independent risk factor for adverse clinical outcomes, but preprocedural predictors of this complication have not been established. This study evaluated the morphological characteristics of culprit lesions by frequency-domain optical coherence tomography (FD-OCT), and examined their predictive value for procedure-related myocardial injury in patients undergoing elective PCI. METHODS: Sixty-eight patients treated by FD-OCT-guided elective PCI were studied. On the basis of the presence or absence of postprocedural plasma cardiac troponin T (cTnT) elevation, patients were divided into elevation (cTnT-E, n=25) and nonelevation (cTnT-nonE, n=43) groups. FD-OCT examinations of culprit lesions were performed before and after stent implantation, and tissue characteristics were evaluated within a 10-mm-long segment of each lesion. RESULTS: Clinical parameters were similar between the two groups. Stent length was significantly longer in the cTnT-E group than in the cTnT-nonE group. On baseline OCT images, thin-cap fibroatheroma and calcium deposition were more frequently observed within culprit segments of the cTnT-E group compared with the cTnT-nonE group (32.0 vs. 11.6%, P=0.043, and 72.0 vs. 46.5%, P=0.039, respectively). In addition, colocalization of these two findings was a powerful predictor of PCI-related cTnT elevation (odds ratio 8.40, 95% confidence interval 1.65-52.78, P<0.01). Further, the predictive value of this colocalization was enhanced when the analysis included only spotty calcification (odds ratio 21.00, 95% confidence interval 2.65-454.22, P=0.003). CONCLUSION: FD-OCT examination showed that colocalization of thin-cap fibroatheroma and spotty calcification was a powerful predictor of PCI-related cTnT elevation. FD-OCT is useful for stratifying risk during PCI to avoid procedure-related complications.

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.

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.

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.

An elevated ratio of placental growth factor to soluble fms-like tyrosine kinase-1 predicts adverse outcomes in patients with stable coronary artery disease.

OBJECTIVE: To investigate the predictive values of placental growth factor (PlGF) and its endogenous antagonist, soluble fms-like tyrosine kinase-1 (sFlt-1), for the long-term prognosis of patients with stable coronary artery disease (CAD). Both PlGF and sFlt-1 play important roles in the pathological mechanisms of atherosclerosis. We recently demonstrated that the plasma levels of these molecules are correlated with the severity of coronary atherosclerosis. METHODS: We enrolled 464 patients with stable CAD who consecutively underwent coronary angiography. Baseline blood samples were collected from the femoral artery immediately before coronary angiography (after the administration of 20 units of heparin), and the plasma levels of PlGF and sFlt-1 were measured. A Cox proportional hazard regression analysis was performed to evaluate the relationship between these parameters and the occurrence of all-cause death (ACD) and total cardiovascular events (TCVE) during a median follow-up of 3.3 years. RESULTS: A total of 31 ACDs and 51 TCVEs occurred. Patients with higher PlGF/sFlt-1 ratios (>4.22×10(-2)) had a significantly higher risk of both ACD and TCVE than patients with lower ratios (<4.22×10(-2)) (hazard ratio [HR]: 3.32, 95% confidence interval [CI]: 1.43 to 7.72, p=0.005, and HR: 2.23, 95% CI: 1.23 to 4.03, p=0.008, respectively). A multivariate analysis showed the PlGF/sFlt-1 ratio to be an independent predictor for ACD, but not TCVE. CONCLUSION: The baseline PlGF/sFlt-1 ratio is an independent predictor of long-term adverse outcomes in patients with stable CAD.

PHD2 regulates arteriogenic macrophages through TIE2 signalling.

Occlusion of the main arterial route redirects blood flow to the collateral circulation. We previously reported that macrophages genetically modified to express low levels of prolyl hydroxylase domain protein 2 (PHD2) display an arteriogenic phenotype, which promotes the formation of collateral vessels and protects the skeletal muscle from ischaemic necrosis. However, the molecular mechanisms underlying this process are unknown. Here, we demonstrate that femoral artery occlusion induces a switch in macrophage phenotype through angiopoietin-1 (ANG1)-mediated Phd2 repression. ANG blockade by a soluble trap prevented the downregulation of Phd2 expression in macrophages and their phenotypic switch, thus inhibiting collateral growth. ANG1-dependent Phd2 repression initiated a feed-forward loop mediated by the induction of the ANG receptor TIE2 in macrophages. Gene silencing and cell depletion strategies demonstrate that TIE2 induction in macrophages is required to promote their proarteriogenic functions, enabling collateral vessel formation following arterial obstruction. These results indicate an indispensable role for TIE2 in sustaining in situ programming of macrophages to a proarteriogenic, M2-like phenotype, suggesting possible new venues for the treatment of ischaemic disorders.

Prognostic value of B-type natriuretic peptide and its amino-terminal proBNP fragment for cardiovascular events with stratification by renal function.

BACKGROUND: Brain natriuretic peptide (BNP) and amino-terminal proBNP (NT-proBNP) are useful biomarkers for diagnosis and prediction of prognosis. Both of these peptides are elevated in patients with chronic kidney disease (CKD), but there is no evidence as to which peptide is the more suitable biomarker in patients with severe renal dysfunction. METHODS AND RESULTS: This retrospective cohort study evaluated patients with cardiovascular diseases (64.9±11.7 years, mean±SD). The end points were all-cause death and a composite end point of all-cause death, nonfatal myocardial infarction, nonfatal stroke, hospitalization for severe heart failure, and initiation of hemodialysis. Baseline plasma BNP and NT-proBNP levels, expressed as log-transformed data, were closely correlated in patients with CKD stages 1-3 (n=998) (r2=0.870, p<0.001), whereas for CKD stages 4-5 (n=85) there was a significant but weaker correlation (r2=0.209, p<0.001). During follow-up periods (51.3±0.4 months), 132 patients died and 202 patients reached the composite end point. The area under the receiver operating characteristic curve (AUROC) for BNP and NT-proBNP were similar for CKD stages 1-3. However, for CKD stages 4-5, the AUC for mortality for BNP was 0.713 and that for NT-proBNP was 0.760, while the AUC for the composite end point for BNP was 0.666 and that for NT-proBNP was 0.720. CONCLUSIONS: Both BNP and NT-proBNP are useful biomarkers for mortality and cardiovascular events, but NT-proBNP may be superior to BNP for CKD stages 4-5.

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.

Gene-targeting of Phd2 improves tumor response to chemotherapy and prevents side-toxicity.

The success of chemotherapy in cancer treatment is limited by scarce drug delivery to the tumor and severe side-toxicity. Prolyl hydroxylase domain protein 2 (PHD2) is an oxygen/redox-sensitive enzyme that induces cellular adaptations to stress conditions. Reduced activity of PHD2 in endothelial cells normalizes tumor vessels and enhances perfusion. Here, we show that tumor vessel normalization by genetic inactivation of Phd2 increases the delivery of chemotherapeutics to the tumor and, hence, their antitumor and antimetastatic effect, regardless of combined inhibition of Phd2 in cancer cells. In response to chemotherapy-induced oxidative stress, pharmacological inhibition or genetic inactivation of Phd2 enhances a hypoxia-inducible transcription factor (HIF)-mediated detoxification program in healthy organs, which prevents oxidative damage, organ failure, and tissue demise. Altogether, our study discloses alternative strategies for chemotherapy optimization.