Hakuoh Konishi

Isolation of Bone Marrow Stromal Cell–Derived Smooth Muscle Cells by a Human SM22α Promoter In Vitro Differentiation of Putative Smooth Muscle Progenitor Cells of Bone Marrow

Background—Bone marrow stromal cells (BMSCs) have many characteristics of mesenchymal stem cells that can differentiate into smooth muscle cells (SMCs). However, there have been few studies closely following the cell development of smooth muscle lineage among BMSCs. Methods and Results—To investigate the possible existence of a cell population committed to the SMC lineage among bone marrow adhesion cells, we tried to detect and follow the in vitro differentiation of such a cell type by using a promoter-sorting method with a human SM22&agr; promoter (−480 bp)/green fluorescent protein (GFP) construct. The construct was transfected to adhesion cells that appeared 5 days after the seeding of mononuclear cells from bone marrow. GFP was first detectable 5 days after the transfection in a cell population [Ad(G) cells], which expressed PDGF-&bgr; but neither mature (calponin) nor immature (SMemb) SMC-specific proteins at that time. However, the cells were eventually grown into individual clones that expressed SMC-specific proteins (&agr;-smooth muscle actin, calponin, and SM-1), suggesting that Ad(G) cells have partly at least progenitor properties. Because early studies have reported that PDGF-&bgr; signaling plays pivotal roles in the differentiation of mesenchymal smooth muscle progenitor cells, Ad(G) cells might be putative mesenchymal smooth muscle progenitors expressing PDGF-&bgr;. Conclusions—We demonstrated the presence of a cell population fated to become SMCs and followed their differentiation into SMCs among BMSCs.

Wavering calcified amorphous tumour of the heart in a haemodialysis patient

Calcified amorphous tumour is a rare, non-neoplastic, endocardially based, intracavitary cardiac mass. This report describes a 59-year old man in whom a mobile mass was found incidentally in the heart by routine echocardiography after he had been on haemodialysis for 3 years. Transoesophageal echocardiography revealed a high-echoic swinging tumour that originated from the annulus of the anterior commissure of the mitral valve. Surgical resection was performed to prevent embolization, and his clinical course was excellent.

Red cell distribution width predicts short- and long-term outcomes of acute congestive heart failure more effectively than hemoglobin

The present study compared short- and long-term prognostic values of red blood cell distribution width (RDW) with those of hemoglobin (Hgb) among patients with acute congestive heart failure (CHF) in a cardiac care unit. The cross-sectional study examined data from 521 patients with acute CHF who were admitted to a cardiac care unit and followed up for 24 months (median). Mean Hgb levels in patients who succumbed (DIH) or remained alive (AIH) were 11.0±1.8 and 11.8±2.6 g/l (P>0.05), respectively. Median values of RDW were 16.2% and 14.4%, respectively (P<0.0001). During the 24-month follow-up, mean levels of Hgb in groups with and without endpoints were 11.4±2.5 and 12.5±2.4 g/dl (P<0.0001), respectively. Median RDW values were 14.9 and 13.8%, respectively (P<0.0001). Logistic regression analysis showed that in-hospital mortality was significantly associated with RDW (P=0.044), New York Heart Association (NYHA) functional class IV (P=0.0037), estimated glomerular filtration rate (eGFR) (P=0.042) and C-reactive protein (P=0.0044), but not with Hgb (P=0.10). The multivariate Cox proportional hazard model selected RDW [hazard ratio (HR), 2.19; P<0.0001], left ventricular ejection fraction (HR 0.81, P=0.0016), age (10-year increase; HR 1.19, P=0.0017) and NYHA functional classes III/IV (HR 1.52, P=0.0029) as independent predictors of long-term outcomes after adjustment, but not Hgb (HR 1.01, P=0.86). Higher RDW values in acute CHF patients at admission were associated with worse short- and long-term outcomes and RDW values were more prognostically relevant than Hgb levels.

Deletion of LR11 Attenuates Hypoxia-Induced Pulmonary Arterial Smooth Muscle Cell Proliferation With Medial Thickening in Mice

Objective—We aimed to determine whether LR11 (low-density lipoprotein receptor with 11 binding repeats) is a potential key regulator of smooth muscle cell (SMC) proliferation during the progression of hypoxia-induced medial thickening in mice and whether sLR11 (soluble LR11) can serve as a biomarker in patients with pulmonary arterial hypertension. Approach and Results—The role of LR11 in pulmonary arterial hypertension was investigated using mouse and cell models of induced hypoxia. The expression of LR11 and of hypoxia-inducible factor-1&agr; was significantly increased in lung tissues from C57Bl/6 mice after 3 weeks of exposure to hypoxia compared with normoxia. Serum sLR11 levels were also increased. Physiological and histochemical analyses showed that increased right ventricular systolic pressure, right ventricular hypertrophy, and medial thickening induced under hypoxia in wild-type mice were attenuated in LR11−/− mice. The proliferation rates stimulated by hypoxia or platelet-derived growth factor-BB were attenuated in SMC derived from LR11−/− mice, compared with those from wild-type mice. Exogenous sLR11 protein increased the proliferation rates of SMC from wild-type mice. The expression of LR11 and hypoxia-inducible factor-1&agr; was increased in cultured SMC under hypoxic conditions, and hypoxia-inducible factor-1&agr; knockdown almost abolished the induction of LR11. Serum sLR11 levels were significantly higher in patients with, rather than without, pulmonary arterial hypertension. sLR11 levels positively correlated with pulmonary vascular resistance and mean pulmonary arterial pressure. Conclusions—LR11 regulated SMC proliferation during the progression of hypoxia-induced medial thickening in mice. The findings obtained from mice, together with those in humans, indicate that sLR11 could serve as a novel biomarker that reflects the pathophysiology of proliferating medial SMC in pulmonary arterial hypertension.

In‑hospital and long‑term outcomes of congestive heart failure: Predictive value of B‑type and amino‑terminal pro‑B‑type natriuretic peptides and their ratio

Relative changes in B-type natriuretic peptide (BNP) and amino terminal pro-BNP (NT-proBNP) levels may help to assess the risk of congestive heart failure (CHF). However, whether these levels at the time of admission enable the prediction of outcomes with acute exacerbation remains unknown. The current study determined the abilities of BNP, NT-proBNP and their ratio to predict in-hospital and long-term outcomes of patients with CHF. Patients who were admitted to the cardiac care unit of Juntendo University Hospital (Tokyo, Japan) with acute CHF onset were consecutively enrolled into the present observational study. Serum levels of BNP and NT-proBNP were immediately measured on admission, and other biomarkers and clinical data were also investigated. Of 195 enrolled patients, 16 (8.2%) succumbed to CHF in hospital and 124 (69.3%) reached the endpoint of mortality or readmission following a median follow-up of 14 months. Multiple linear regression analysis revealed body mass index, low density lipoprotein cholesterol, hemoglobin, estimated glomerular filtration rate and C-reactive protein as independent predictors of the NT-proBNP/BNP ratio. BNP, NT-proBNP and their ratio were significantly higher among those who succumbed to CHF than in those who remained alive in hospital (P<0.05). Logistic regression analysis indicated that the ratio was an independent predictor for in-hospital mortality and long-term outcomes. In conclusion, the ratio of NT-proBNP to BNP more effectively predicts in-hospital outcomes than either factor alone and it may also help to predict outcomes among patients with acute exacerbation of HF.

LR11 PLAYS A PIVOTAL ROLE IN PULMONARY A ARTERIAL HYPERTENSION

This study examined low-density lipoprotein receptor relative with 11 binding repeats (sLR11) plays a pivotal role in pulmonary arterial hypertension (PAH). LR11 (also called SorLA or SORL1), is a low-density lipoprotein (LDL)-receptor that is expressed in intimal smooth muscle cells during the

RED CELL DISTRIBUTION WIDTH IS BETTER FOR PREDICTING SHORT-TERM AND LONG-TERM OUTCOMES THAN HAEMOGLOBIN IN ACUTE ONSET OF CONGESTIVE HEART FAILURE

Objectives The goal of this study was to determine the short-term and long-term prognostic value of red cell distribution width (RDW) in congestive heart failure (CHF) patients hospitalised in cardiac care unit and to compare the value of haemoglobin (Hgb) levels. Methods In a cross-sectional study, patients with acute onset of CHF and admitted to cardiac care unit in Juntendo University Hospital were enrolled from Jan 2007 to Dec 2009 and were followed for a median of 24 months (range 6–42 months). We measured red blood cell distribution width, haemoglobin and other biomarkers when admission. The results were statistically analysed by software JMP 8.0 and SPSS 18.0. Results A total of 521 patients were enrolled, with a median (IQR) age of 72 (64, 80) years old (66.6% male). Multivariate analysis showed that Hgb, B-type natriuretic peptide (BNP), estimated glomerular filtration rate (eGFR) and high density lipoprotein cholesterol (HDL-C) were independent predictors of RDW. The mean level of Hgb in in-hospital-dead group was 11.0±1.8 g/dl and 11.8±2.6 g/dl in in-hospital alive group (p>0.05), and the median (IQR) value of RDW was 16.2% (15.1%, 17.6%) and 14.4% (13.5%, 15.8%), respectively (p<0.0001). Through a median of 24 months follow up, the mean level of Hgb in no-endpoint-group was 12.5±2.4 g/dl and 11.4±2.5 g/dl in endpoint-group (p<0.0001), and the median (IQR) value of RDW was 13.8% (13.3%, 14.4%) and 14.9% (13.9%, 16.5%), respectively (p<0.0001). Logistic regression analysis showed in-hospital mortality was significantly related with RDW (p=0.044), NYHA IV (p=0.0037), eGFR (p=0.042) and C response protein (p=0.0044), not with Hgb (p=0.10). In the final multivariate cox proportional hazard models, RDW (per SD increase, HR 2.19, 95% CI 1.92 to 2.50, p<0.0001), left ventricular ejection fraction (per SD increase, HR 0.81, 95% CI 0.71 to 0.92, p=0.0016), age (10 years increase, HR 1.19, 95% CI 1.07 to 1.34, p=0.0017) and NYHA III/IV (HR 1.52, 95% CI 1.15 to 2.03, p=0.0029) remained independent predictors of long-term outcomes after adjustment, while Hgb did not add prediction value (per SD increase, HR 1.01, 95% CI 0.96 to 1.13, p=0.86). Conclusions Higher red cell distribution width values at admission in congestive heart failure patients were associated with worse short-term and long-term outcomes, with more prognostic value than haemoglobin. RDW is inexpensive and contained in routine test. It should be included in multi-markers prognostic models to predict short-term and long-term outcomes in patients with acute exacerbation of heart failure.