Koichi Akutsu

Unblinded Pilot Study of Autologous Transplantation of Bone Marrow Mononuclear Cells in Patients With Thromboangiitis Obliterans

Background— The short-term clinical benefits of bone marrow mononuclear cell transplantation have been shown in patients with critical limb ischemia. The purpose of this study was to assess the long-term safety and efficacy of bone marrow mononuclear cell transplantation in patients with thromboangiitis obliterans. Methods and Results— Eleven limbs (3 with rest pain and 8 with an ischemic ulcer) of 8 patients were treated by bone marrow mononuclear cell transplantation. The patients were followed up for clinical events for a mean of 684±549 days (range 103 to 1466 days). At 4 weeks, improvement in pain was observed in all 11 limbs, with complete relief in 4 (36%). Pain scale (visual analog scale) score decreased from 5.1±0.7 to 1.5±1.3. An improvement in skin ulcers was observed in all 8 limbs with an ischemic ulcer, with complete healing in 7 (88%). During the follow-up, however, clinical events occurred in 4 of the 8 patients. The first patient suffered sudden death at 20 months after transplantation at 30 years of age. The second patient with an incomplete healing of a skin ulcer showed worsening of the lesion at 4 months. The third patient showed worsening of rest pain at 8 months. The last patient developed an arteriovenous shunt in the foot at 7 months, which spontaneously regressed by 1 year. Conclusions— In the present unblinded and uncontrolled pilot study, long-term adverse events, including death and unfavorable angiogenesis, were observed in half of the patients receiving bone marrow mononuclear cell transplantation. Given the current incomplete knowledge of the safety and efficacy of this strategy, careful long-term monitoring is required for future patients receiving this treatment.

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.

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.

A case of streptococcal toxic shock syndrome due to Group G streptococci identified as Streptococcus dysgalactiae subsp. equisimilis

A 79-year-old man with a 3-month history of lymphedema of the lower limbs, and diabetes mellitus, was admitted to our hospital for suspected deep venous thrombosis. Several hours after admission, leg pain and purpura-like skin color appeared. On the 2nd hospital day, he was referred to our department for possible acute occlusive peripheral artery disease (PAD) and skin necrosis with blisters; however, computed tomography with contrast showed no occlusive lesions. He had already developed shock and necrotizing deep soft-tissue infections of the left lower leg. Laboratory findings revealed renal dysfunction and coagulation system collapse. Soon after PAD was ruled out, clinical findings suggested necrotizing deep soft-tissue infections, shock state, disseminated intravascular coagulation, and multiple organ failure. These symptoms led to a high suspicion of the well-recognized streptococcal toxic shock syndrome (STSS). With a high suspicion of STSS, we detected Group G β-hemolytic streptococci (GGS) from samples aspirated from the leg bullae, and the species was identified as Streptococcus dysgalactiae subsp. equisimilis (SDSE) by 16S-ribosomal RNA sequencing. However, unfortunately, surgical debridement was impossible due to the broad area of skin change. Despite adequate antimicrobial therapy and intensive care, the patient died on the 3rd hospital day. The M-protein gene (emm) typing of the isolated SDSE was revealed to be stG6792. This type of SDSE is the most frequent cause of STSS due to GGS in Japan. We consider it to be crucial to rapidly distinguish STSS from acute occlusive PAD to achieve life-saving interventions in patients with severe soft-tissue infections.

High prevalence of vertebral artery tortuosity of Loeys-Dietz syndrome in comparison with Marfan syndrome.

PurposeLoeys-Dietz syndrome (LDS) is a connective tissue disease caused by mutations in the genes encoding the transforming growth factor-β receptor (TGFBR). LDS is associated with aneurysms or dissections of the aorta similar to Marfan syndrome (MFS) as well as arterial tortuosity and aneurysms in the peripheral arteries. The purpose of this study was to evaluate the arterial diseases of LDS to differentiate it from MFS.Materials and methodsA total of 10 LDS patients with an identified mutation in TGFBR (6 male, 4 female; mean age 36.3 years) and 20 MFS patients with an identified mutation in fibrilin-1 who were age- and sex-matched to the LDS subjects (12 male, 8 female; mean age 37.1 years) were reviewed. The prevalence of vertebral arterial tortuosity (VAT) and peripheral aneurysm (PAN) was studied using computed tomography angiography.ResultsIn all, 9 of the 10 LDS patients had VAT, and five PANs were observed in 3 patients. In contrast, 8 (40%) of the MFS patients had VAT, and 1 patient had a PAN. LDS had a higher prevalence of VAT (P = 0.017) by Fisher’s exact test.ConclusionThe VAT was highly prevalent among LDS patients. Thus, the presence of VAT has the potential to differentiate LDS from MFS.

Acute Type B Aortic Dissection With Communicating vs. Non-Communicating False Lumen

BACKGROUND In practice, patients with acute aortic dissection (AAD) are generally divided into 2 groups according to the status of the false lumen: non-communicating or communicating. The similarities and differences between the 2 groups, however, have not been fully determined in a large population. METHODS AND RESULTS: We studied 502 patients with Stanford type B AAD. Clinical background at symptom onset was compared, and similarities and differences characterized, for patients with non-communicating (NC group, n=288) vs. communicating (C group, n=214) false lumens. Time of day (00.00-06.00 hours, 06.00-12.00 hours, 12.00-18.00 hours, and 18.00-24.00 hours) and extent of physical activity (extreme exertion, slight exertion, at rest, and sleeping) at symptom onset were similar between groups. Patients in the NC group were older (mean age, 71±11 years vs. 64±14 years, P<0.01) and had lower prevalence of distally extended aortic dissection (26% vs. 8%, P<0.01) and deaths in hospital (2% vs. 7%, P=0.011) than those in the C group. CONCLUSIONS At symptom onset, clinical circumstances and physical activity were similar between the groups, and old age and a background of DeBakey IIIa aortic dissection may be associated with determination of false lumen status. The outcome in the NC group was better than in the C group.

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.