Engineering calcium deposits on polycaprolactone scaffolds for intravascular applications using primary human osteoblasts

Total atherosclerotic occlusions often include significant calcium deposits. Current animal models do not mimic the pathology of gradual occlusion of arteries and lack cell‐mediated calcium. The primary goal of this project was to establish an animal model incorporating these features into chronic total occlusions, using biodegradable scaffolds. As the first step, this study sought to determine the optimal dosage of TGF‐β1 on polycaprolactone (PCL) scaffolds cultured with primary human osteoblasts (HOBs) to effectively induce in vitro calcification. HOBs were cultured in TGF‐β1 and dexamethsaone (Dex)‐supplemented medium in well plates. Calcium in the cultures was visualized using alizarin red. The highest calcification was observed in groups with both TGF‐β1 (0.02 ng/ml) and Dex (10^?10 M ) in the medium. Next, HOBs were cultured on PCL scaffolds with different loadings of TGF‐β1: 0 (control), 5, 10, 50 and 100 ng. These cultures were performed with or without Dex (10^?10 M ) in the medium. DNA content, ALP activity and the amount and distribution of calcium were examined at 7, 14, 21 and 28 days. TGF‐β1 appeared to have an inhibitory effect on scaffold calcification when grown in Dex‐supplemented medium. When cultured without Dex, the lower amount of TGF‐β1 loading (5 ng) showed the most calcification, high DNA synthesis and high ALP activity on scaffolds. This study demonstrates the potential of implanting a PCL–HOB construct in an animal artery to establish a model of atherosclerotic occlusion with calcification. Copyright © 2010 John Wiley & Sons, Ltd.     

Live/Real Time Three‐Dimensional Transesophageal Echocardiographic Findings in Caseous Mitral Annular Calcification

We describe a 77‐year‐old female with hypertrophic cardiomyopathy in whom live/real time three‐dimensional transesophageal echocardiography (3DTEE) provided incremental value over two‐dimensional transthoracic and transesophageal echocardiography (2DTTE, 2DTEE) and three‐dimensional transthoracic echocardiography (3DTTE) in making a more comprehensive assessment and a more confident diagnosis of caseous mitral annular calcification. 3DTEE revealed a portion of the mass to consist of small, multiple, highly echogenic discrete band‐like and punctate areas within a relatively much less echogenic stroma and surrounded by a well defined highly echogenic border. This appearance correlated with the pathological findings of calcific granules/strands located in a liquefied or semiliquefied interior providing a typical toothpaste like appearance. The highly echogenic outer border represented the residual outer portion or rim of the calcific mass which did not undergo liquefaction. These findings on 3DTEE which correlated with the toothpaste like appearance seen at surgery were not visualized on 2DTTE, 2DTEE, and 3DTTE. (Echocardiography 2010;27:1147‐1150)     

Association of the I148M/PNPLA3 (rs738409) polymorphism with premature coronary artery disease,fatty liver,and insulin resistance in type 2 diabetic patients and healthy controls. The GEA study

The aim of this study was to evaluate the potential use of the I148M/PNPLA3 (rs738409) gene polymorphism as a susceptibility marker for premature coronary artery disease (pCAD) and/or cardiovascular risk factors in Mexican type 2 diabetes mellitus patients (T2DM). The polymorphism was genotyped by 5′ exonuclease TaqMan assays in a group of 2572 subjects (1103 with pCAD and 1469 healthy controls) belonging to the Genetics of Atherosclerotic Disease (GEA) Mexican Study. Anthropometric and biochemical measurements were performed in all individuals. The association between the I148M/PNPLA3 (rs738409) gene polymorphism with pCAD and other metabolic and cardiovascular risk factors was evaluated using logistic regression analysis under different statistical approaches including dominant, recessive, heterozygous, additive, and co-dominant models. The polymorphism was not associated with pCAD in the whole group of participants, however, when patients and controls were divided into those with and without T2DM, under additive model, the polymorphism was associated with the presence of pCAD only in patients with T2DM (OR = 1.20, 95% CI: 1.01–1.42, P_add = 0.042). On the other hand, under several models adjusted for age, gender, body mass index and T2DM, the polymorphism was associated with increased risk of fatty liver and elevated levels of alanine transaminase (ALT) in the whole group of pCAD patients and controls. In the control group, the polymorphism was associated with insulin resistance and coronary artery calcification (CAC) score ≥ 10 under several models. The results suggest that the I148M/PNPLA3 (rs738409) polymorphism is associated with the presence of pCAD in T2DM patients and with some cardiometabolic parameters. The association detected with CAC in the control group indicates that this polymorphism could be a marker for subclinical atherosclerosis.     

Cavernous hemangioma of the stomach: A case report and review of the literature

A cavernous hemangioma of the stomach in a 41-year-old Japanese man was reported. The patient had numerous hemorrhagic telangiectasias in the skin and was also diagnosed as having a submucosal tumor of the stomach by an incidental upper gastrointestinal X-ray study. Wedge resection of the stomach was performed. The tumor was located in the submucosal, proper muscular and subserosal layers. The resected specimen showed proliferation of vascular spaces lined with a layer of endothelial cells and filled with red blood cells together with a partially calcified thrombus. The histopathologic diagnosis was cavernous hemangioma of the stomach with calcified thrombus. The patient has been doing well for twenty years. We report the case and briefly review the literature. This study is supported in part by a Grant from Federation of National Public Service and Affiliated Personnel Mutual Aid Association, Tokyo, Japan.     

Radial augmentation index is related to cardiovascular risk in hemodialysis patients

Cardiovascular accidents related to atherosclerosis are the leading cause of death among hemodialysis patients, which makes continuous monitoring of their cardiovascular status crucial. Recently, a handy device for monitoring the augmentation index (AIx) in the radial artery was introduced in Japan, enabling the use of the AIx in addition to pulse wave velocity (PWV) in the management of hemodialysis patients. In this study the AIx, PWV, abdominal aortic calcification index (ACI), and left ventricular mass index (LVMI) were serially assessed in 108 hemodialysis patients. The radial AIx was monitored using a newly introduced tonometer (HEM-9010AI), and the interrelationships among the measured parameters and their contributions to the risk of cardiovascular accidents were evaluated. The radial AIx was significantly higher in hemodialysis patients than in healthy subjects (N = 50) and was well correlated with risk markers such as LVMI (r = 0.30, P = 0.019) and ACI (r = 0.38, P < 0.001), but not with PWV. Multiregression analysis showed that radial AIx was also significantly associated with LVMI, ACI and blood pressure; PWV was associated with other parameters such as age, blood pressure, and ACI. The AIx and ACI were both significantly increased in patients with cardiovascular complications. Although PWV was strongly increased in the hemodialysis patients, it failed to discriminate between these subgroups of high-risk patients. The radial AIx is closely associated with aortic calcification, cardiac hypertrophy, and a history of cardiovascular accidents in hemodialysis patients, and could be a useful marker for management of these patients.     

Prospective Evaluation of Transseptal TMVR for Failed Surgical Bioprostheses: MITRAL Trial Valve-in-Valve Arm 1-Year Outcomes

ObjectivesThe aim of this study was to assess 1-year clinical outcomes among high-risk patients with failed surgical mitral bioprostheses who underwent transseptal mitral valve-in-valve (MViV) with the SAPIEN 3 aortic transcatheter heart valve (THV) in the MITRAL (Mitral Implantation of Transcatheter Valves) trial.BackgroundThe MITRAL trial is the first prospective study evaluating transseptal MViV with the SAPIEN 3 aortic THV in high-risk patients with failed surgical mitral bioprostheses.MethodsHigh-risk patients with symptomatic moderate to severe or severe mitral regurgitation (MR) or severe mitral stenosis due to failed surgical mitral bioprostheses were prospectively enrolled. The primary safety endpoint was technical success. The primary THV performance endpoint was absence of MR grade ≥2+ or mean mitral valve gradient ≥10 mm Hg (30 days and 1 year). Secondary endpoints included procedural success and all-cause mortality (30 days and 1 year).ResultsThirty patients were enrolled between July 2016 and October 2017 (median age 77.5 years [interquartile range (IQR): 70.3 to 82.8 years], 63.3% women, median Society of Thoracic Surgeons score 9.4% [IQR: 5.8% to 12.0%], 80% in New York Heart Association functional class III or IV). The technical success rate was 100%. The primary performance endpoint in survivors was achieved in 96.6% (28 of 29) at 30 days and 82.8% (24 of 29) at 1 year. Thirty-day all-cause mortality was 3.3% and was unchanged at 1 year. The only death was due to airway obstruction after swallowing several pills simultaneously 29 days post-MViV. At 1-year follow-up, 89.3% of patients were in New York Heart Association functional class I or II, the median mean mitral valve gradient was 6.6 mm Hg (interquartile range: 5.5 to 8.9 mm Hg), and all patients had MR grade ≤1+.ConclusionsTransseptal MViV in high-risk patients was associated with 100% technical success, low procedural complication rates, and very low mortality at 1 year. The vast majority of patients experienced significant symptom alleviation, and THV performance remained stable at 1 year.     

Asymptomatic chronic intestinal ischemia caused by idiopathic phlebosclerosis of mesenteric vein

Phlebosclerosis of the mesenteric vein is a rare condition causing chronic intestinal ischemia, it has only been reported in Japan. A 56-year-old man with liver cirrhosis and hepatic tumor presented with phlebosclerosis of mesenteric vein without any abdominal symptoms. He was admitted for examination of suspected hepatic tumor. Abdominal plain x-ray films and computed tomography revealed calcification of the mesenteric vein. Barium enema revealed narrowing and thumbprinting from the cecum to transverse colon. On colonoscopic examination, blue-black vessels were visible in the terminal ileum, and hyperemic nodular mucosa with small irregular ulcers surrounded by dark purple mucosa was found from the cecum to transverse colon. The etiology of mesenteric vein phlebosclerosis is unknown, although a physical mechanism rather than inflammatory changes appear to be involved in this rare and usually progressive condition of chronic intestinal ischemia.     

Update and Mutational Analysis of SLC20A2: A Major Cause of Primary Familial Brain Calcification

Primary familial brain calcification (PFBC) is a heterogeneous neuropsychiatric disorder, with affected individuals presenting a wide variety of motor and cognitive impairments, such as migraine, parkinsonism, psychosis, dementia, and mood swings. Calcifications are usually symmetrical, bilateral, and found predominantly in the basal ganglia, thalamus, and cerebellum. So far, variants in three genes have been linked to PFBC: SLC20A2, PDGFRB, and PDGFB. Variants in SLC20A2 are responsible for most cases identified so far and, therefore, the present review is a comprehensive worldwide summary of all reported variants to date. SLC20A2 encodes an inorganic phosphate transporter, PiT‐2, widely expressed in various tissues, including brain, and is part of a major family of solute carrier membrane transporters. Fifty variants reported in 55 unrelated patients so far have been identified in families of diverse ethnicities and only few are recurrent. Various types of variants were detected (missense, nonsense, frameshift) including full or partial SLC20A2 deletions. The recently reported SLC20A2 knockout mouse will enhance our understanding of disease mechanism and allow for screening of therapeutic compounds. In the present review, we also discuss the implications of these recent exciting findings and consider the possibility of treatments based on manipulation of inorganic phosphate homeostasis.