Tsuyoshi Yoshimuta

Mutation of ACTA2 gene as an important cause of familial and nonfamilial nonsyndromatic thoracic aortic aneurysm and/or dissection (TAAD)

Approximately 20% of aortic aneurysm and/or dissection (AAD) cases result from inherited disorders, including several systemic and syndromatic connective‐tissue disorders, such as Marfan syndrome, Ehlers‐Danlos syndrome, and Loeys‐Dietz syndrome, which are caused by mutations in the FBN1, COL3A1, and TGFBR1 and TGFBR2 genes, respectively. Nonsyndromatic AAD also has a familial background, and mutations of the ACTA2 gene were recently shown to cause familial AAD. In the present study, we conducted sequence analyses of the ACTA2 gene in 14 unrelated Japanese patients with familial thoracic AAD (TAAD), and in 26 with sporadic and young‐onset TAAD. Our results identified three mutations of ACTA2, two novel [p.G152_T205del (c.616+1G>T), p.R212Q] and one reported (p.R149C), in the 14 patients with familial TAAD, and a novel mutation (p.Y145C) of ACTA2 in the 26 sporadic and young‐onset TAAD patients, each of which are considered to be causative for TAAD. Some of the clinical features of these patients were the same as previously reported, whereas others were different. These findings confirm that ACTA2 mutations are important in familial TAAD, while the first sporadic and young‐onset TAAD case with an ACTA2 mutation was also identified. Hum Mutat 30:1–6, 2009.

Differences in Atherosclerotic Profiles Between Patients With Thoracic and Abdominal Aortic Aneurysms

Differences in atherosclerotic profiles between patients with thoracic aortic aneurysm (TAA) and patients with abdominal aortic aneurysm (AAA) have not been studied. We retrospectively studied the clinical records of 343 consecutive patients (132 TAA and 211 AAA) who were admitted to our hospital for elective repair of aortic aneurysms between July 2001 and December 2004. Clinical variables were compared between patients with TAA and those with AAA by using a univariate analysis, and those achieving statistical significance were subsequently assessed in a multivariate analysis. The incidence of coronary artery disease (CAD) (53% vs 23%, p <0.0001), 3-vessel coronary disease (41% vs 10%, p <0.0001), male gender (86% vs 74%, p <0.01), smoker (88% vs 76%, p <0.01), chronic obstructive pulmonary disease (COPD) (30% vs 15%, p <0.01), and diabetes mellitus (39% vs 23%, p <0.01) were significantly higher in patients with AAA than in those with TAA. In contrast, the incidence of hypertension (91% vs 81%, p <0.05), saccular-type aneurysm (61% vs 7%, p <0.0001), and body mass index (24.1 +/- 3.1 vs 23.2 +/- 3.5, p <0.05) were significantly higher in patients with TAA than in those with AAA. Multivariate stepwise logistic analysis revealed that CAD (odds ratio [OR] 3.65; 95% confidence interval [CI] 2.12 to 6.42; p <0.0001), COPD (OR 2.05; 95% CI 1.11 to 3.89; p <0.05), and diabetes mellitus (OR 1.85; 95% CI 1.06 to 3.27; p <0.05) were associated with AAA, and that body mass index (OR 9.39; 95% CI 2.0 to 46.8; p <0.01), hypertension (OR 3.09; 95% CI 1.48 to 6.87; p <0.01), and cerebral infarction (OR 2.83; 95% CI 1.25 to 6.50; p <0.05) were associated with TAA. In conclusion, atherosclerotic profiles are significantly different between patients with TAA and patients with AAA. This result suggests the possibility that mechanisms underlying the development of aortic aneurysms may differ between TAA and AAA, and, from the perspective of prevention, provides further stimulus for the modification of key risk factors for atherosclerosis.

Expression Profiling of the Ephrin (EFN) and Eph Receptor (EPH) Family of Genes in Atherosclerosis-Related Human Cells

Ephrin B1 and its cognate receptor, Eph receptor B2, key regulators of embryogenesis, are expressed in human atherosclerotic plaque and inhibit adult human monocyte chemotaxis. Few data exist, however, regarding the gene expression profiles of the ephrin (EFN) and Eph receptor (EPH) family of genes in atherosclerosis-related human cells. Gene expression profiles were determined of all 21 members of this gene family in atherosclerosis-related cells by reverse transcription—polymerase chain reaction analysis. The following 17 members were detected in adult human peripheral blood monocytes: EFNA1 and EFNA3 – EFNA5 (coding for ephrins A1 and A3 – A5); EPHA1, EPHA2, EPHA4 – EPHA6 and EPHA8 (coding for Eph receptors A1, A2, A4 – A6 and A8); EFNB1 and EFNB2 (coding for ephrins B1 and B2); and EPHB1 – EPHB4 and EPHB6 (coding for Eph receptors B1 – B4 and B6). THP-1 monocytic cells, Jurkat T cells and adult arterial endothelial cells also expressed multiple EFN and EPH genes. These results indicate that a wide variety of ephrins and Eph receptors might affect monocyte chemotaxis, contributing to the development of atherosclerosis. Their pathological significance requires further study.

Assessment of Coronary Atherosclerosis in Patients With Familial Hypercholesterolemia by Coronary Computed Tomography Angiography

The aims of this study were (1) to determine whether the accumulation of coronary plaque burden assessed with coronary computed tomography angiography (CCTA) can predict future events and (2) to estimate the onset and progression of coronary atherosclerosis in patients with familial hypercholesterolemia (FH). Consecutive 101 Japanese patients with heterozygous FH (men = 52, mean age 56 ± 16 years, mean low-density lipoprotein cholesterol 264 ± 58 mg/dl) who underwent 64-detector row CCTA without known coronary artery disease were retrospectively evaluated by assigning a score (0 to 5) to each of 17 coronary artery segments according to the Society of Cardiovascular Computed Tomography guidelines. Those scores were summed and subsequently natural log transformed. The periods to major adverse cardiac events (MACE) were estimated using multivariable Cox proportional hazards models. During the follow-up period (median 941 days), 21 MACE had occurred. Receiver operating characteristic curve analyses identified a plaque burden score of 3.35 (raw score 28.5) as the optimal cutoff for predicting a worse prognosis. Multivariate Cox regression analysis identified the presence of a plaque score ≥3.35 as a significant independent predictor of MACE (hazard ratio = 3.65; 95% confidence interval 1.32 to 25.84, p <0.05). The regression equations were Y = 0.68X - 15.6 (r = 0.54, p <0.05) in male and Y = 0.74X - 24.8 (r = 0.69, p <0.05) in female patients with heterozygous FH. In conclusion, coronary plaque burden identified in a noninvasive, quantitative manner was significantly associated with future coronary events in Japanese patients with heterozygous FH and that coronary atherosclerosis may start to develop, on average, at age 23 and 34 years in male and female patients with heterozygous FH, respectively.

Usefulness of Fibrinogen/Fibrin Degradation Product to Predict Poor One-Year Outcome of Medically Treated Patients With Acute Type B Aortic Dissection

Previous studies have indicated that medical therapy provides excellent outcomes for patients with uncomplicated Stanford type B acute aortic dissection. However, affected aortas are often compromised by aneurysmal dilatation and rupture, resulting in poor outcomes. The purpose of this study was to determine predictors of aortic events in patients with Stanford type B acute aortic dissection receiving conservative medical therapy. The study group consisted of 78 consecutive patients with Stanford type B acute aortic dissection who were admitted to the hospital within 48 hours of onset. These patients were treated medically and followed up for 1 year. Aortic events were defined as rupture, recurrent dissection, aortic expansion with diameter>or=60 mm, rapid aortic expansion at a rate of >or=10 mm/yr, and the development of visceral or limb ischemia. Predictors of these events were determined using multivariate analyses. During 1-year follow-up, aortic events were observed in 13 (17%) patients, including aortic rupture in 3 (4%), aortic diameter>or=60 mm in 4 (5%), rapid expansion of the aorta in 3 (4%), and the development of visceral or limb ischemia in 3 (4%). On multivariate analysis, fibrinogen-fibrin degradation product level>or=20 microg/ml (odds ratio 7.802, 95% confidence interval 1.405 to 43.335) on admission was the only independent predictor of aortic events at 1 year. In conclusion, careful monitoring is required for patients with medically treated Stanford type B acute aortic dissection associated with fibrinogen-fibrin degradation product level>or=20 microg/ml on admission.

Prevalence and Predictors of Coexistent Silent Atherosclerotic Cardiovascular Disease in Patients With Abdominal Aortic Aneurysm Without Previous Symptomatic Cardiovascular Diseases

Although patients with abdominal aortic aneurysm (AAA) often have other cardiovascular diseases (CVDs), the exact prevalence remains unclear. We aimed to determine the prevalence and predictors of coexistent silent atherosclerotic cardiovascular diseases (SACVDs) in patients with AAA without a history of CVD. Consecutive 157 patients with AAA (mean age, 73 years), without any previous history of CVD, were included. Silent myocardial ischemia (SMI), cerebrovascular disease (CeVD), peripheral artery disease (PAD), and thoracic aortic aneurysm (TAA) without symptoms coexisted in 29.3%, 25.5%, 15.9%, and 8.3%, respectively. The significant predictors of SMI were diabetes mellitus (P = .025) and male sex (P = .048). The significant predictor of silent CeVD was older age (P = .039). The borderline predictors of asymptomatic PAD and TAA were diabetes mellitus (P = .056) and AAA size (P = .053), respectively. Even with no previous symptomatic CVD, patients with AAA have high prevalence of coexistent SACVD.

Characteristics in Phenotypic Manifestations of Genetically Proved Marfan Syndrome in a Japanese Population

Diagnosis of Marfan syndrome (MS) is made according to the Ghent nosology, which is based on data from European and American populations. The validity of applying the Ghent nosology to other than Western populations is an ongoing discussion because there may be racial differences in basic physical features. The validity of applying the Ghent nosology to patients other than Westerners suspected of having MS was examined. One hundred thirteen Japanese patients who were suspected of having MS and underwent genetic analysis were examined to see whether they fulfilled the Ghent nosology. Of 113 patients, MS was diagnosed in 58 patients/51 probands. Of these 51 probands, 46 (90%) showed mutations in the Fibrillin-1 gene(FBN1) and were enrolled in this study. The frequency of each manifestation of Ghent nosology in the Japanese population was compared with those reported in the FBN1 Universal Mutation Database that was mainly obtained from the Western population (n = 1,013 probands). Frequencies were lower in the Japanese population than the Western population of the manifestations of arm span to height ratio >1.05 (20% vs 55%; p <0.01), scoliosis (40% vs 53%; p <0.05), reduced extension at elbows (2% vs 16%; p <0.05), and joint hypermobility (46% vs 63%; p <0.05). In conclusion, we found a lower frequency of skeletal manifestations of MS in Japanese patients than reported in the database for Western patients with MS. It was possible that the diagnosis of MS according to the Ghent nosology for Japanese patients was underestimated, especially for skeletal involvements.

Impact of Elevated D-Dimer on Diagnosis of Acute Aortic Dissection With Isolated Neurological Symptoms in Ischemic Stroke

BACKGROUND Plasma D-dimer is known to be a useful clinical marker of thrombogenic status, and D-dimer is used as a diagnostic marker for acute aortic dissection (AAD). Little is known, however, regarding the clinical value of D-dimer for diagnosis of asymptomatic AAD in patients with ischemic stroke. We investigated whether D-dimer could be used for early diagnosis of AAD with isolated neurological symptoms in ischemic stroke patients. METHODS AND RESULTS We evaluated a total of 1,236 consecutive patients with symptomatic ischemic stroke without chest or back pain who underwent either head computed tomography or magnetic resonance imaging. D-dimer was measured within 24 h after onset. There were 9 patients with Stanford type A AAD and they had significantly higher D-dimer than the patients without AAD (mean, 46.47±54.48 μg/ml; range, 6.9-167.1 μg/ml vs. 2.33±3.58 μg/ml, 0.3-57.9 μg/ml, P<0.001). When a cut-off of 6.9 μg/ml was adopted for d-dimer on the basis of receiver operating characteristics analysis, the sensitivity and specificity for AAD were 100% and 94.8%, respectively, while the positive and negative predictive values were 14.7% and 100%, respectively. CONCLUSIONS D-dimer might be a useful marker for the early diagnosis of AAD with isolated neurological symptoms in ischemic stroke patients. Whole-body contrast-enhanced computed tomography should be performed in ischemic stroke patients who have high D-dimer.

Corkscrew collaterals in Buerger’s disease

A 62-year-old man with Buerger’s disease presented with worsening of intermittent claudication in his right limb. By conventional colour Doppler examination, the posterior tibial artery (PTA) appeared contiguous and nonobstructed (Figure 1, large arrows). Corkscrew arteries could not be visualized due to low resolution (small arrow). In contrast, advanced dynamic flow examination using Aplio SSA-700A (Toshiba, Japan) clearly demonstrated characteristic arterial features of Buerger’s disease (Figure 2). First, the flow signal of the PTA was not contiguous (large arrows), suggesting multiple recanalization of organized thrombus, which is often seen in the chronic stage of Buerger’s disease. Second, the flow signal within the PTA disappeared at the origin of the corkscrew artery (open arrow). Third, the corkscrew artery existed outside of the lumen of the PTA (small arrows). These suggested that the corkscrew artery represented a collateral vessel, which ran alongside the obstructed PTA. Figure 1 Figure 2 Recanalization of the thrombosed vessel and the presence of corkscrew collaterals around areas of segmental occlusion are characteristic features of Buerger’s disease (1,2). Conventional colour Doppler examination, however, cannot document the blood flow within tiny vessels because of the low resolution and low frame rates. Advanced dynamic flow images are very similar to B-mode images and can depict tiny vessels due to high resolution, wide dynamic range and high frame rates. Directional flow information can also be obtained in different colours. Advanced dynamic flow examination in the present patient provided visualization of the recanalized arterial segment and corkscrew collateral vessel circumventing the occlusion. This technique may be applied for noninvasive diagnosis of Buerger’s disease.

“String of Beads” Appearance of Bilateral Brachial Artery in Fibromuscular Dysplasia

A 56-year-old woman presented with chest discomfort and underwent coronary angiography via a transradial route. Left brachial artery stenosis was suspected because of difficulty in passing with a 0.035-inch guide wire. Upper-extremity angiography showed presence of multiple stenoses and aneurysmal dilatations in her brachial artery (Figure 1). Subsequent to catheterization, the patient received duplex scanning using Aplio SSA-700A (Toshiba, Tokyo, Japan) using the advanced dynamic flow …