Characteristics, Antithrombotic Patterns, and Prognostic Outcomes in Claudication and Critical Limb-Threatening Ischemia Undergoing Endovascular Therapy.

PURPOSE: The underlying difference between intermittent claudication (IC) and critical limb-threatening ischemia (CLTI) still remains unclear. This prospective multicenter observational study aimed to clarify differences in clinical features and prognostic outcomes between IC and CLTI, and prognostic factors in patients undergoing endovascular therapy (EVT). MATERIALS AND METHODS: A total of 692 patients with 808 limbs were enrolled from 20 institutions in Japan. The primary measurements were the 3-year rates of major adverse cardiovascular event (MACE) and reintervention. RESULTS: Among patients, 79.0% had IC and 21.0% had CLTI. Patients with CLTI were more frequently women and more likely to have impaired functional status, undernutrition, comorbidities, hypercoagulation, hyperinflammation, distal artery disease, short single antiplatelet and long anticoagulation therapies, and late cilostazol than patients with IC. Aortoiliac and femoropopliteal diseases were dominant in patients with IC and infrapopliteal disease was dominant in patients with CLTI. Patients with CLTI underwent less frequently aortoiliac intervention and more frequently infrapopliteal intervention than patients with IC. Longitudinal change of ankle-brachial index (ABI) exhibited different patterns between IC and CLTI (pinteraction=0.002), but ABI improved after EVT both in IC and in CLTI (p<0.001), which was sustained over time. Dorsal and plantar skin perfusion pressure in CLTI showed a similar improvement pattern (pinteraction=0.181). Distribution of Rutherford category improved both in IC and in CLTI (each p<0.001). Three-year MACE rates were 20.4% and 42.3% and 3-year reintervention rates were 22.1% and 46.8% for patients with IC and CLTI, respectively (log-rank p<0.001). Elevated D-dimer (p=0.001), age (p=0.043), impaired functional status (p=0.018), and end-stage renal disease (p=0.019) were independently associated with MACE. After considering competing risks of death and major amputation for reintervention, elevated erythrocyte sedimentation rate (p=0.003) and infrainguinal intervention (p=0.002) were independently associated with reintervention. Patients with CLTI merely showed borderline significance for MACE (adjusted hazard ratio 1.700, 95% confidence interval 0.950-3.042, p=0.074) and reintervention (adjusted hazard ratio 1.976, 95% confidence interval 0.999-3.909, p=0.05). CONCLUSIONS: The CLTI is characterized not only by more systemic comorbidities and distal disease but also by more inflammatory coagulation disorder compared with IC. Also, CLTI has approximately twice MACE and reintervention rates than IC, and the underlying inflammatory coagulation disorder per se is associated with these outcomes. CLINICAL IMPACT: The underlying difference between intermittent claudication (IC) and critical limb-threatening ischemia (CLTI) still remains unclear. This prospective multicenter observational study, JPASSION study found that CLTI was characterized not only by more systemic comorbidities and distal disease but also by more inflammatory coagulation disorder compared to IC. Also, CLTI had approximately twice major adverse cardiovascular event (MACE) and reintervention rates than IC. Intriguingly, the underlying inflammatory coagulation disorder per se was independently associated with MACE and reintervention. Further studies to clarify the role of anticoagulation and anti-inflammatory therapies will contribute to the development of post-interventional therapeutics in the context of peripheral artery disease.

Mobile mural thrombus and spontaneous echo contrast in ascending aorta after postoperative adjuvant cisplatin-based chemotherapy.

A 70-year-old asymptomatic male who had undergone a right nephrectomy for renal pelvic cancer was referred to us with a thrombus in the ascending aorta detected by contrast-enhanced computed tomography after chemotherapy with gemcitabine/cisplatin. Transesophageal echocardiography revealed a 4-cm mobile mural thrombus in the ascending aorta. An emergency thoracotomy for planned aortic root replacement was performed, but the intraoperative epi-aortic ultrasound indicated that the thrombus had disappeared, and it showed prominent spontaneous-echo contrast (SEC) in the ascending aorta. We speculate that vascular endothelium damage due to the cisplatin-based chemotherapy induced the thrombus and SEC in the ascending aorta.

A Case of Left Atrial Myxoma Whose Initial Symptom Was Finger Ischemic Symptom.

We experienced a 45-year-old Japanese man who was transferred to our hospital complaining of acute onset of pain and pallor in the right lower limb. Two years earlier, he had complained of repetitive pain at rest and pallor in the left third and fourth fingers. The physical exam and angiography demonstrated occlusion of finger arteries, however we could not reach final diagnosis. Acute arterial occlusive disease in the right lower limb was suspected. Transthoracic echocardiography demonstrated a gross tumor in the left atrium, which suggested left atrial myxoma. An emergency tumorectomy was successfully conducted. Pathologically, the fragile tumor and resultant thrombosis could have caused the patient's peripheral circulatory failure at least two years prior to this episode. A rigorous systemic survey is important even when the ischemic symptom is localized in peripheral circulation.

Internal medicine board certification and career pathways in Japan.

BACKGROUND: Establishing and managing a board certification system is a common concern for many countries. In Japan, the board certification system is under revision. The purpose of this study was to describe present status of internal medicine specialist board certification, to identify factors associated with maintenance of board certification and to investigate changes in area of practice when physicians move from hospital to clinic practice. METHODS: We analyzed 2010 and 2012 data from the Survey of Physicians, Dentists and Pharmacists. We conducted logistic regression analysis to identify factors associated with the maintenance of board certification between 2010 and 2012. We also analyzed data on career transition from hospitals to clinics for hospital physicians with board certification. RESULTS: It was common for physicians seeking board certification to do so in their early career. The odds of maintaining board certification were lower in women and those working in locations other than academic hospitals, and higher in physicians with subspecialty practice areas. Among hospital physicians with board certification who moved to clinics between 2010 and 2012, 95.8% remained in internal medicine or its subspecialty areas and 87.7% maintained board certification but changed their practice from a subspecialty area to more general internal medicine. CONCLUSION: Revisions of the internal medicine board certification system must consider different physician career pathways including mid-career moves while maintaining certification quality. This will help to secure an adequate number and distribution of specialists. To meet the increasing demand for generalist physicians, it is important to design programs to train specialists in general practice.

A Case of Adult-Onset Acute Rheumatic Fever With Long-Lasting Atrioventricular Block Requiring Permanent Pacemaker Implantation.

A 45-year-old hypertensive Japanese woman presented with epigastric pain on inspiration, fever, complete atrioventricular block and polyarthritis. Her antistreptolysin O levels were markedly elevated. A diagnosis of rheumatic fever was made according to the modified Jones criteria. She was prescribed loxoprofen sodium, which was partially effective for her extracardiac clinical symptoms. However, she had syncope due to complete atrioventricular block with asystole longer than 10 seconds. Consequently, we implanted a permanent pacemaker. Although we prescribed prednisolone, the efficacy of which was limited for the patient's conduction disturbance, the complete atrioventricular block persisted. In our systematic review of 12 similar cases, the duration of complete heart block was always transient and there was no case requiring a permanent pacemaker. We thus encountered a very rare case of adult-onset acute rheumatic fever with persistent complete atrioventricular block necessitating permanent pacemaker implantation.

The effect of refresher training on fact description in medical incident report writing in the Japanese language.

To maintain the effectiveness of the training (1st-Training Session: 1st-TS) to accurate describe facts in the medical incident reports (IRs) in Japanese, a refresher TS was designed and its effectiveness was examined. First, textual analysis showed that IRs' accuracy significantly decreased six months after the 1st-TS. Based on this result, the refresher TS was designed and conducted with 64 residents. To verify the refresher TS' effectiveness, IRs after the 1st-TS, six months later, and after the refresher TS were compared via text analysis. The results showed that the refresher TS restored the description rate of patient's background, safety check procedures, original work procedures, information on equipment used, reporter's actions, and post-incident response. The questionnaire was also administered and showed that the refresher TS contributed to residents' motivation to learn about IRs. In conclusion, the refresher TS contributed to sustaining the effect of the 1st-TS on accurately describing IRs.

Disaster hypertension: experience from the great East Japan earthquake of 2011.

After a major disaster, such as the East Japan Earthquake with ensuing tsunami and nuclear accident in March 2011, there is typically a spike in cardiovascular disease onset due to increased blood pressure and hypercoagulability. The risk of cardiovascular disease after an earthquake can be reduced by understanding the characteristics of these risks and taking appropriate preventive and remedial measures. During the East Japan Earthquake disaster, Disaster Cardiovascular Prevention (DCAP) Risk Scores (0-6 points; goal ≤4 points)/Prevention Scores (0-8 points; goal ≥ 6 points) were used to identify patients at risk at shelters and then safeguard their living conditions, chiefly by monitoring blood pressure and offering appropriate lifestyle guidance as well as treatment. By quickly reducing elevated blood pressures and then assuring stable control we could prevent the mortality and morbidity associated with disaster hypertension. This paper reviews the disaster-related mechanisms that induce cardiovascular disease and introduces the DCAP system and four typical cases in which it intervened.

Training residents in medical incident report writing to improve incident investigation quality and efficiency enables accurate fact gathering.

We assessed whether training on writing readable and accurate medical incident reports (IRs) improves the quality of fact description. In this training, 124 residents created fictional IRs. We provided tips, including using When, Where, Who, What, Why, How. We compared the fictional IRs with and without tips, and the trainees' and non-trainees' IRs submitted in the first five months after training. Results indicated that the subject words in IRs were more clarified and the readability was improved. The fictional IRs using tips were more accurate, with increased descriptions of the patient's background, reporter's actions, team members' actions and conversations, safety check procedures, result of the error, and post-incident response. The reporter's actions, work procedures, and environment were more clarified in the trainees' IRs than in the non-trainees' IRs. This training may help analysts comprehend the sequence of and underlying factors for reporter's actions based on IRs.

Growth Differentiation Factor 15 Predicts Cancer Death in Patients With Cardiovascular Risk Factors: The J-HOP Study.

Background: Disease-related anorexia-cachexia is associated with poor prognosis of patients with cardiovascular disease (CVD) or cancer. Growth differentiation factor-15 (GDF-15) has emerged as a central regulator of appetite and body weight. However, the exact role of GDF-15 in lean patients has not been elucidated. Aim: Our aim is to evaluate whether the association of GDF-15 with mortality, including cancer death, differs according to body mass index (BMI) level. Methods and Results: We collected blood samples from 4,061 patients with CV risk factors who were enrolled in the nationwide practice-based J-HOP (Japan Morning Surge-Home Blood Pressure) study. Serum GDF-15 levels were determined by immunoassay analysis. During a mean follow-up period of 6.6 years, we observed 174 (6.7/1000 person-year) all-cause deaths, 68 (2.6/1000 person-year) cancer deaths, and 56 (2.2/1000 person-year) CV deaths. Patients were stratified according to the cut-points of GDF-15 at 1,200 ng/L and BMI at 22.5 and 25.0 kg/m2. The association between the GDF-15/BMI based study groups and each outcome was evaluated by Cox-proportional hazard models with adjustment for established risk factors. The multivariate Cox regression model showed that patients with elevated GDF-15 (≥1,200 ng/L) and low BMI (<22.5 kg/m2) were significantly associated with increased risk of all outcomes [all-cause death, hazard ratio (HR) 3.15, 95% confidence interval (CI) 1.85-5.34, p < 0.001; cancer death, HR 3.52, 95%CI 1.64-7.57, p = 0.001; CV death, HR 2.88, 95%CI 1.20-6.92, p = 0.018, respectively] compared to a reference group with non-elevated GDF-15 and normal BMI (22.5-25.0 kg/m2). In analyses of a subgroup with low BMI (<22.5 kg/m2), patients with elevated GDF-15 had 4.79-fold increased risk of cancer death and 11-fold greater risk of CV death when compared with patients with non-elevated GDF-15 (<1,200 ng/L) after adjustment for established risk factors. Conclusion: In patients with CV risk factors, GDF-15 was associated with all-cause, cancer, and CV death. This relationship was especially remarkable in patients with low BMI. The serum GDF-15 levels in patients with low BMI might be a useful marker to identify the potential for anorexia-cachexia associated with CVD and cancer.

Mönckeberg's sclerosis.

Contrast-enhanced computed tomography angiography reveals "railroad track-like" calcifications bilaterally from the femoral to the popliteal arteries.

Growth Differentiation Factor-15 Predicts Death and Stroke Event in Outpatients With Cardiovascular Risk Factors: The J-HOP Study.

Background Growth differentiation factor-15 (GDF-15) has emerged as a novel biomarker to predict all-cause death in community-dwelling individuals and patients with cardiovascular disease. We evaluated the prognostic value of GDF-15 in outpatients with cardiovascular risk factors. Methods and Results GDF-15 levels were measured in 3562 outpatients with cardiovascular risk factors in the J-HOP (Japan Morning Surge-Home Blood Pressure) study, a nationwide prospective study. Participants were stratified according to tertiles of GDF-15 and followed up for all-cause death and cardiovascular disease. During a mean follow-up period of 6.6 years, there were 155 all-cause deaths, 81 stroke events including cerebral infarction and intracranial hemorrhage, and 141 cardiac events including cardiac artery disease and heart failure. Patients with higher GDF-15 levels were associated with risks of all-cause death and stroke events (except for cardiac events) after adjustment for traditional risk factors and other prognostic biomarkers (NT-proBNP [N-terminal pro-B-type natriuretic peptide], high-sensitivity troponin T; all-cause death, hazard ratio, 2.38; 95% CI, 1.26-4.48; P=0.007; stroke events, hazard ratio, 2.93; 95% CI, 1.31-6.56, P=0.009; compared with the lowest tertile). Furthermore, incorporating GDF-15 to the predictive models for all-cause death improved discrimination and reclassification significantly. For stroke events, GDF-15 showed similar diagnostic accuracy to NT-proBNP and high-sensitivity troponin T. Conclusions In Japanese outpatients with cardiovascular risk factors, GDF-15 improves risk stratification for all-cause death when compared with NT-proBNP and high-sensitivity troponin T. GDF-15 was associated with increased risks of stroke events beyond conventional risk factors and other prognostic markers; however, the predictive ability for stroke events was equivalent to NT-proBNP and high-sensitivity troponin T. Registration URL: http://www.umin.ac.jp/ctr.; Unique identifier: UMIN000000894.

Salt Intake and Risk of Disaster Hypertension Among Evacuees in a Shelter After the Great East Japan Earthquake.

This study investigated the association between salt intake and risk of disaster hypertension. We analyzed the data of surveys evaluating the health condition of evacuees in shelters after the Great East Japan Earthquake on April 30 and May 5, 2011. Among 272 subjects who completed the basic health condition questionnaire and underwent a medical examination, 158 (58%) had disaster hypertension (systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg). Average estimated sodium intake assessed by spot urine was significantly associated with disaster hypertension (odds ratio per 1 g/d, 1.16; 95% CI, 1.05-1.30). When we defined the high risk factors for salt-sensitive hypertension as older age (≥65 years), obesity (body mass index, ≥25 kg/m2), chronic kidney disease, and diabetes mellitus, estimated sodium intake was found to be a risk factor for disaster hypertension in the total group (odds ratio per 1 g/d, 1.27; 95% CI, 1.12-1.43) and even in the group without prevalent hypertension before disaster (n=146; odds ratio per 1 g/d, 1.46; 95% CI, 1.19-1.79). There was an interaction between estimated sodium intake and disaster hypertension according to the presence or absence of high risk of salt-sensitive hypertension in the group without prevalent hypertension (P=0.03). Disaster hypertension conferred a risk of microalbuminuria (odds ratio, 3.00; 95% CI, 1.71-5.26; P<0.001). We conclude that increased estimated sodium intake was associated with disaster hypertension in evacuees after disaster. This association was noted in the population with high risk of salt-sensitive hypertension and without prevalent hypertension before natural disaster. Additionally, disaster hypertension was associated with subclinical organ damage.

Adeno-associated virus vector-mediated systemic interleukin-10 expression ameliorates hypertensive organ damage in Dahl salt-sensitive rats.

BACKGROUND: Inflammation plays an important role in the pathogenesis of hypertension and hypertensive organ damage. Interleukin (IL)-10, a pleiotropic anti-inflammatory cytokine, exerts vasculoprotective effects in many animal models. In the present study, we examined the preventive effects of adeno-associated virus (AAV) vector-mediated sustained IL-10 expression against hypertensive heart disease and renal dysfunction in Dahl salt-sensitive rats. METHODS: We injected the rats intramuscularly with an AAV type 1-based vector encoding rat IL-10 or enhanced green fluorescent protein (EGFP) at 5 weeks of age; subsequently, the rats were fed a high-sodium diet from 6 weeks of age. RESULTS: Sustained IL-10 expression significantly improved survival rate of Dahl salt-sensitive rats compared with EGFP expression (62.5% versus 0%, p < 0.001); it also caused 26.0% reduction in systolic blood pressure at 15 weeks (p < 0.0001). Echocardiography exhibited a 22.0% reduction in hypertrophy (p < 0.0001) and a 26.3% improvement in fractional shortening (p < 0.0001) of the rat left ventricle in the IL-10 group compared to the EGFP group. IL-10 expression also caused a 21.7% decrease in the heart weight/body weight index and cardiac atrial natriuretic peptide levels. Histopathological studies revealed that IL-10 decreased inflammatory cell infiltration, fibrosis, and transforming growth factor-beta(1) levels in the failing heart. Furthermore, IL-10 expression significantly reduced urine protein excretion with increased glomerular filtration rates. CONCLUSIONS: This is the first study to demonstrate that the anti-inflammatory cytokine IL-10 has a significant anti-hypertensive effect. AAV vector-mediated IL-10 expression potentially prevents the progression of refractory hypertension and hypertensive organ damage in humans.

Life- and limb-saving endovascular therapy in a patient with acute abdominal aortic occlusion.

A 79-year-old man developed severe bilateral ischemic symptoms in the lower limbs. Chest-abdominal-pelvic contrast computed tomography (CT) showed acute occlusion involving the abdominal aorta, and endovascular therapy (EVT) was used as emergency treatment. Two self-expandable stents placed in the thrombus area resulted in restoration of blood flow to the lower limbs, despite limited stent expansion, and movement of these limbs. Follow-up CT showed good stent expansion. The patient had a favorable recovery without additional surgery. This case suggests that EVT might be an additional option for acute abdominal aortic occlusion if surgery or thrombolytic therapies are not possible.

Interleukin-10-mediated inhibition of angiogenesis and tumor growth in mice bearing VEGF-producing ovarian cancer.

Interleukin-10 (IL-10) is an immunosuppressive cytokine produced by T lymphocytes and drawing attention as an inhibitor of tumor angiogenesis. In this study, we investigated antiangiogenic and tumor suppressive effects of IL-10 in ovarian cancer cells. mIL-10-expressing plasmid was transferred into two ovarian cancer cell lines, SHIN-3 [vascular endothelial growth factor (VEGF) producing] and KOC-2S (non-VEGF producing). After selection, mIL-10-expressing cells were obtained as SHIN-3/mIL-10 and KOC-2S/mIL-10. No significant differences were observed in in vitro growth properties between mIL-10-expressing cells and control (luciferase expressing) cells in either KOC-2S or SHIN-3. The angiogenic activities of mIL-10-expressing cells were measured by dorsal air sac assay, which detected the number of newly formed blood vessels within a chamber in vivo. In addition, tumor formation was evaluated by s.c. tumor transplantation, and survival was monitored after i.p. injection of ovarian cancer cells into BALB/c nude mice. Both in vivo angiogenic activity and tumor growth were significantly inhibited in SHIN-3/mIL-10 cells compared with the control. Moreover, peritoneal dissemination was inhibited, and the survival period was significantly prolonged (mean survival days > 90 versus 36). In contrast, in the case of KOC-2S cells, no significant differences were observed in any of the parameters tested. These results indicate that IL-10 has suppressive effects on angiogenesis, tumor growth, and peritoneal dissemination of VEGF-producing ovarian cancer cells. Although the mechanisms of the antiangiogenic effect of IL-10 are still unclear, the potential usefulness of IL-10-mediated gene therapy of ovarian cancer was suggested.

Cardiac sarcoidosis, the complete atrioventricular block of which was completely recovered by intravenous steroid pulse therapy.

Atrioventricular block (AVB) in individuals with cardiac sarcoidosis (CS) is one of the major complications caused by inflammation of the conducting system of the heart, as a sign of worse prognosis. We report the case of a 53-year-old Japanese woman whose electrocardiogram showed complete AVB by the clinical diagnosis of CS. We administered intravenous methylpredonisolone (1 g/day) for 3 days. On the second day of steroid pulse therapy, the complete AVB improved to sinus rhythm of 1st degree AVB and complete right bundle branch block. Normal sinus rhythm was then observed after oral steroid therapy. These results suggest that in cases of complete AVB, steroid pulse therapy with a strong anti-inflammatory effect may be recommended first. .

Long sleep duration: a nonconventional indicator of arterial stiffness in Japanese at high risk of cardiovascular disease: the J-HOP study.

Long and short sleep durations were reported as independently associated with hypertension, aortic stiffness, and cardiovascular disease. High-sensitivity C-reactive protein (hs-CRP) was shown to be associated with increased aortic stiffness. Here, we investigated the relationship between self-reported sleep duration and pulse wave velocity (PWV) in the elderly at high risk of cardiovascular disease. We also investigated whether hs-CRP moderates this relationship. Among 4310 patients with ≥1 cardiovascular risks recruited for the Japan Morning Surge-Home Blood Pressure Study, a questionnaire including items on daily sleep duration was completed. We measured the brachial-ankle PWV (baPWV) and hs-CRP levels in 2304 of these patients (mean age 64.7 years, 49.6% males). In accord with the patients' sleep duration (<6 hours, ≥6 to <8 hours, and ≥8 hours per night), significant associations between sleep duration and the PWV were observed (1594 vs. 1644 vs. 1763 cm/s, P < .0001). In the multiple regression analysis adjusted for age, body mass index, total cholesterol, HbA1c and clinic systolic blood pressure, long sleep duration (≥8 hours per night) (P < .05), and log hs-CRP (P < .05) were significantly positively associated with PWV when the patients with 6- to 8-hour sleep duration were defined as a reference group. Significant interactions of long sleep duration by age and that by antihypertensive medication for baPWV were observed. The effect of long sleep on PWV was greatest in the oldest age group. Long sleep duration and hs-CRP were significant indicators of increased baPWV in this elderly high-risk Japanese population. Age and antihypertensive medication use were significant modulators of the relationship between long sleep duration and arterial stiffness.

Identification of serum soluble ST2 receptor as a novel heart failure biomarker.

BACKGROUND: Using genomic technology, we previously identified an interleukin-1 receptor family member, ST2, as a gene markedly induced by mechanical strain in cardiac myocytes. The soluble receptor form of ST2 is secreted and detectable in human serum. This study tested the hypothesis that soluble ST2 levels in the serum of patients with severe chronic heart failure are increased in patients with neurohormonal activation. METHODS AND RESULTS: Serum samples, clinical variables, and neurohormone levels from the PRAISE-2 heart failure trial (NYHA functional class III-IV; end point, mortality or transplantation) were analyzed. ST2 serum measurements were performed with ELISA on samples from 161 patients obtained at trial enrollment and from 139 of the same patients obtained 2 weeks after trial enrollment. Baseline ST2 levels were correlated with baseline B-type natriuretic peptide (BNP) levels (r=0.36, P<0.0001), baseline proatrial natriuretic peptide (ProANP) levels (r=0.36, P<0.0001), and baseline norepinephrine levels (r=0.39, P<0.0001). The change in ST2 was significant as a univariate predictor of subsequent mortality or transplantation (P=0.048), as was baseline BNP (P<0.0001) and baseline ProANP (P<0.0001). In multivariate models including BNP and ProANP, the change in ST2 remained significant as a predictor of mortality or transplantation independent of BNP and ProANP. CONCLUSIONS: Serum soluble ST2 is a novel biomarker for neurohormonal activation in patients with heart failure. In patients with severe chronic NYHA class III to IV heart failure, the change in ST2 levels is an independent predictor of subsequent mortality or transplantation.