Efficacy and Safety of Warfarin for the Treatment of Venous Thromboembolism　- A Multicenter Prospective Observational Cohort Study in Japan (AKAFUJI Study).

BACKGROUND: A large-scale prospective study of the efficacy and safety of warfarin for the treatment of venous thromboembolism (VTE) has not been conducted in Japan. Therefore, we conducted a real-world prospective multicenter observational cohort study (AKAFUJI Study; UMIN000014132) to investigate the efficacy and safety of warfarin for VTE.Methods and Results: Between May 2014 and March 2017, 352 patients (mean [±SD] age 67.7±14.8 years; 57% female) with acute symptomatic/asymptomatic VTE were enrolled; 284 were treated with warfarin. The cumulative incidence of recurrent symptomatic VTE was higher in patients without warfarin than in those treated with warfarin (8.7 vs. 2.2 per 100 person-years, respectively; P=0.018). The cumulative incidence of bleeding complications was not significantly different between the 2 groups. The mean prothrombin time-international normalized ratio (PT-INR) during warfarin on-treatment was <1.5 in 180 patients, 1.5-2.5 in 97 patients, and >2.5 in 6 patients. The incidence of bleeding complications was significantly higher in patients with PT-INR >2.5, whereas the incidence of recurrent VTE was not significantly different between the 3 PT-INR groups. The cumulative incidence of recurrent VTE and bleeding complications did not differ significantly among those in whom VTE was provoked by a transient risk factor, was unprovoked, or was associated with cancer. CONCLUSIONS: Warfarin therapy with an appropriate PT-INR according to Japanese guidelines is effective without increasing bleeding complications, regardless of patient characteristics.

Difference in right and left cardio-ankle vascular index as a useful marker for evaluation of leg ischemia in patients with lower extremity arterial disease.

OBJECTIVES: Cardio-ankle vascular index (CAVI) is a blood pressure-independent measure of heart-ankle pulse wave velocity and is used as an indicator of arterial stiffness. However, there is a paradox that CAVI is inversely associated with leg ischemia in patients with lower extremity arterial disease (LEAD). The aim of this study was to clarify the significance of the absolute value of left and right difference in CAVI (diff-CAVI). METHODS: The subjects were 165 patients with LEAD who had received medication therapy. Relationships between diff-CAVI and leg ischemia were investigated. Leg ischemia was evaluated by decrease in leg arterial flow using ankle-brachial index (ABI) and by symptoms using the Rutherford classification. RESULTS: There was a significant inverse correlation between diff-CAVI and ABI. The odds ratio for low ABI of the 3rd versus 1st tertile groups of diff-CAVI was 7.03 with a 95% confidence interval of 2.71 ∼ 18.22. In ROC analysis, the cutoff value of diff-CAVI for low ABI was 1.05 with a sensitivity of 61.1% and a specificity of 87.1%. The median of diff-CAVI was significantly higher in subjects with grade 2 of the Rutherford classification than in subjects with its grade 1. CONCLUSIONS: diff-CAVI showed an inverse association with ABI and a positive association with symptoms of leg ischemia. Thus, diff-CAVI is thought to be a useful indicator of leg ischemia in LEAD patients.

Relationships of Leg Ischemia Symptoms and Carotid Artery Atherosclerosis with Hypertensive-Disorders-of-Pregnancy-Associated Peptides in Patients with Lower Extremity Arterial Disease.

Objectives: We have proposed seven peptides with low molecular weights in blood as biomarkers for the diagnosis of hypertensive disorders of pregnancy (HDP). The purpose of this cross-sectional study was to investigate the relationships of the HDP-associated peptides with symptoms of leg ischemia and degree of atherosclerosis in patients with lower extremity arterial disease (LEAD). Methods: The subjects were 165 outpatients with LEAD (145 men and 20 women aged 74.3 ± 8.1 years [47-93 years]). Their symptoms of leg ischemia, leg arterial flow, and degree of atherosclerosis were evaluated using the Rutherford classification of Clinical Ischemia Category, ankle-brachial index (ABI) and the intima-media thickness (IMT) of carotid arteries, respectively. Serum concentrations of the HDP-related peptides were measured by mass spectrometry. Results: The grade of the Rutherford classification was positively associated with levels of the peptides with m/z 2091 and 2378 and was inversely associated with levels of the peptide with m/z 2081. The category of the Rutherford classification was inversely associated with ABI. There were no HDP-associated peptides that showed significant relationships with IMT. Conclusions: The peptides with m/z 2081, 2091, and 2378 are possible biomarkers of leg ischemia but are not associated with carotid atherosclerosis in LEAD patients.

[Tricuspid valve endocarditis following osteomyelitis; report of a case].

A 71-year-old man was admitted with complaints of high fever and lumbago. Echocardiography showed vegetation about 16×7 mm in size attached to the tricuspid valve. Magnetic resonance imaging showed osteomyelitis. As serial echocardiography showed the progression of valvular lesion despite antibiotic therapy, the patient underwent endoscopic removal of intervertebral disc 1st, and then tricuspid valve plasty was performed 3 days later. As of the last follow-up observation at 3 years, the patient has been doing well.

[Perforated aneurysm of the non-coronary cusp with aortic regurgitation in a patient with infective endocarditis; report of a case].

This case report describes a 77-year-old man who developed infective endocarditis resulting in perforated aneurysm of the non-coronary cusp with aortic regurgitation. Diagnosis was made by transesophageal echocardiogram and successful surgical valve replacement was performed.

Associations of habitual alcohol drinking with HDL cholesterol and D-dimer in patients with peripheral arterial disease.

BACKGROUND: The risk of cardiovascular disease is lower in light-to-moderate alcohol drinkers than in nondrinkers in the general population. However, it remains to be clarified whether these beneficial effects of alcohol are shown in patients with peripheral arterial disease (PAD). METHODS: The subjects were 153 male outpatients with PAD and they were divided by frequency of drinking into nondrinkers, occasional drinkers (1-4 days/wk) and regular drinkers (5-7 days/wk). Relationships of alcohol drinking with variables related to progression of atherosclerosis and cardiovascular risk were investigated. RESULTS: The levels of HDL cholesterol and d-dimer were significantly higher and lower, respectively, in regular drinkers than in nondrinkers, while there were no significant differences in BMI, blood pressure, total cholesterol, LDL cholesterol, triglycerides, hemoglobin A1c, platelet count, fibrinogen, ankle brachial index and intima-media thickness of the carotid artery in non-, occasional and regular drinkers. Odds ratios of regular drinkers vs. nondrinkers for low HDL cholesterol (0.24 [0.08 âˆ¼ 0.70]) and high d-dimer (0.29 [0.14 âˆ¼ 0.61]) were significantly lower than the reference level. CONCLUSIONS: In patients with PAD, habitual alcohol drinking was associated with increase of HDL cholesterol and suppression of blood coagulability. However, progression of atherosclerosis was not different in nondrinkers and drinkers.

Paradox of the Relationship between Cardio-Ankle Vascular Index and Ankle-Brachial Index in Patients with Lower Extremity Artery Disease.

Objectives: Measurements of ankle-brachial index (ABI) and toe-brachial index (TBI) are standard examinations for evaluating arterial blood flow in lower extremities and diagnosing lower extremity artery disease (LEAD). It remains to be clarified whether cardio-ankle vascular index (CAVI), a blood pressure-independent parameter of arterial stiffness, is associated with ABI and TBI in patients with LEAD. Methods: The subjects were 165 outpatients with LEAD. Arterial blood flow in lower extremities was evaluated by using ABI, TBI, and the degree of leg exercise-induced reduction of ABI (%). Results: CAVI showed significant positive correlations with ABI and TBI and showed significant inverse correlations with exercise-induced % decrease in ABI. CAVI was significantly higher in the 3rd tertile groups of ABI and TBI than that in the corresponding 1st tertile groups and was significantly lower in the 3rd tertile group of exercise-induced % decrease in ABI than that in the 1st tertile group. The above relationships remained significant after adjustment for age, body mass index, blood pressure, diabetes history, and habitual smoking. Conclusions: Although CAVI is a general parameter reflecting arterial stiffness, CAVI showed paradoxical associations, namely, positive associations with ABI and TBI and an inverse association with exercise-induced % decrease in ABI in patients with LEAD.

Peptides associated with hypertensive disorders of pregnancy as possible biomarkers for severity of lower extremity arterial disease.

BACKGROUND AND AIMS: Seven circulating peptides, consisting of 18-28 amino acids, were identified as possible biomarkers of hypertensive disorders of pregnancy (HDP) in our previous study. However, it is unknown whether these peptides are relevant to cardiovascular disease. The purpose of this study was to clarify the relationships between serum levels of these peptides and leg arterial blood flow in patients with lower extremity arterial disease (LEAD). METHODS: The subjects were 165 outpatients with LEAD. Patients with advanced LEAD (stages 5 and 6 of the Rutherford classification) were not included. Leg arterial blood flow was evaluated by ankle brachial pressure index (ABI) and % decrease in ABI after leg exercise induced by a leg loader or treadmill. Concentrations of the seven peptides with m/z 2081 (P-2081), 2091 (P-2091), 2127 (P-2127), 2209 (P-2209), 2378 (P-2378), 2858 (P-2858) and 3156 (P-3156) were measured simultaneously with a mass spectrometer. RESULTS: P-2081, P-2127 and P-2209 levels showed significant positive correlations with leg arterial blood flow, while P-2091, P-2378 and P-2858 levels showed significant inverse correlations with leg arterial blood flow. There was no significant correlation between P-3156 levels and leg arterial blood flow. The above positive and inverse associations between peptide levels and leg arterial blood flow were also found in logistic regression analysis using tertile groups divided by the concentrations of each peptide. CONCLUSIONS: Serum levels of six HDP-related peptides (P-2081, P-2091, P-2127, P-2209, P-2378 and P-2858) were associated with lower extremity arterial blood flow in patients with LEAD, and thus these peptides are possible biomarkers for severity of LEAD.

[Ascending aortic aneurysm associated with von recklinghausen disease].

We report a case of ascending aortic aneurysm complicated with von Recklinghausen disease. A 57-year-old man was referred to our institution for further evaluation of the atrial fibrillation. Computed tomography (CT) revealed an aneurysm of the ascending aorta. The patient underwent resection of aneurysm to prevent rupture. Vascular complications in von Recklinghausen disease and the treatment for the vessels were discussed.

[Thoracoabdominal aortic thrombi as a source of peripheral embolization; report of a case].

We reported a case of peripheral embolization arising from diffuse thoracoabdominal aortic thrombi with minimal evidence for atherosclerosis or other aortic pathology. After the patient was treated with anticoagulation therapy, surgical removal of peripheral embolus was performed.

[Residual inferior sinus venosus atrial septal defect after surgical closure of atrial septal defect; report of a case].

Sinus venosus atrial septal defect( SVD) represent 5~10% of atrial septal defect( ASD). In contrast to the more common superior type in which the superior vena cava overrides the pathological interatrial communication, the inferior type with overriding inferior vena cava is extremely rare. We describe a case of residual inferior SVD after surgical closure of ASD.

[Mixed type ( type + pseudo) left ventricular aneurysm; report of a case].

True left ventricular aneurysms are thought to arise from the expansion and thinning of the transmural infarct area, whereas false aneurysms result from containment of ventricular rupture by pericardial adhesions. We reported a case of true left ventricular aneurysm with pseudoaneurysm( mixed type aneurysm) which was treated surgically.

Association of Serum Uric Acid Levels with Leg Ischemia in Patients with Peripheral Arterial Disease after Treatment.

AIM: We investigated the relationships of serum uric acid levels with the progression of atherosclerosis in patients with peripheral arterial disease (PAD) after treatment. METHODS: Subjects were male patients diagnosed with PAD. Atherosclerosis at the common carotid artery was evaluated based on its intima-media thickness (IMT). Leg arterial flow was evaluated by measuring ankle-brachial index (ABI) and exercise-induced decrease in ABI. RESULTS: Among various risk factors including age, blood pressure, adiposity, estimated glomerular filtration rate, and blood lipid, blood glucose, uric acid, fibrinogen and C-reactive protein levels, only uric acid levels showed significant correlations with ABI [Pearson's correlation coefficient, -0.292 (p＜0.01)] and leg exercise-induced decrease in ABI [Pearson's correlation coefficient, 0.236 (p＜ 0.05)]. However, there was no significant correlation between uric acid levels and maximum or mean IMT. Odds ratios of subjects with the 3rd tertile versus subjects with the 1st tertile for uric acid levels were significantly higher than the reference level of 1.00 for low ABI [4.44 (95% confidence interval, 1.45-13.65, p＜0.01)] and for high % decrease in ABI after exercise [4.31 (95% confidence interval, 1.34-13.82, p＜0.05)]. The associations of uric acid levels with the indicators of leg ischemia were also found after adjustment for age, history of revascularization therapy, diabetes, smoking, alcohol consumption, body mass index, triglyceride levels, and renal function. CONCLUSION: Uric acid levels are associated with the degree of leg ischemia in patients with PAD. Further interventional studies are needed to determine whether the correction of uric acid levels is effective in preventing the progression of PAD.

[Aneurysms of the anterior communicating artery and subclavian artery in association with congenital absence of unilateral internal carotid artery].

We encountered a rare case of unilateral internal carotid arterial defect complicated with anterior communicating aneurysm and subclavian artery aneurysm. The patient was a 56-year-old man in whom cerebral angiography and 3D-CTA revealed defects in the right internal carotid artery and the right carotid canal, and an unruptured aneurysm in the anterior communicating artery. In addition, the patient was also found to have an unruptured aneurysm in the right subclavian artery. As both the aneurysms were considered to have a high risk of rupture and such subclavian aneurysms were likely to cause an embolism, radical surgery was performed for each aneurysm. The postoperative course was uneventful, and the patient was discharged without ambulatory limitations. Although the defect in the internal carotid artery is a relatively rare vascular deformity, the incidence of cerebral aneurysm is about 30% in such cases due to the marked hemodynamic stress involved. On the other hand, there have been only two previous case reports of internal carotid arterial defect complicated with a subclavian aneurysm. Moreover, there have been no previous reports of internal carotid arterial defect complicated with both an intracranial aneurysm and a subclavian aneurysm, as observed in the present case. Thus, this case was very rare and is reported here.

[Recent Knowledge of Smoking and Peripheral Arterial Disease in Lower Extremities].

Peripheral arterial disease (PAD) is an atherosclerotic obstructive disease of the arteries in lower extremities. Patients with PAD show high rates of mortality from coronary artery disease (CAD) and stroke. Smoking as well as diabetes is an important risk factor for PAD. A lesion of PAD in the lower extremities tends to be more proximal in smokers than in nonsmokers and to be more distal in patients with diabetes than in nondiabetics. By a systematic review, the odds ratio for PAD of smokers vs nonsmokers has been reported to be in the range of 1.7-7.4. Previous epidemiological studies suggest a stronger association of smoking with PAD than that with CAD. Nitric oxide (NO) is an important molecule suppressing the progression of atherosclerosis, but this function is compromised by smoking. Smoking decreases the bioactivity of NO and the expression level of NO synthase. In addition, smoking results in deteriorations of risk factors for atherosclerosis such as decreases in blood HDL (high-density lipoprotein) cholesterol and tissue plasminogen activator levels and increases in the levels of blood triglycerides, LDL (low-density lipoprotein) cholesterol, fibrinogen and the von Willebrand factor. Thus, smoking increases blood coagulability and deteriorates the blood lipid profile, resulting in thrombogenetic proneness and dyslipidemia. Smoking also increases the generation of atherogenic oxidized LDL in blood and decreases antiatherogenic prostacyclin production in the vascular endothelium. Smoking cessation is important for the prevention and therapy of PAD, and to this end, counseling by physicians and nicotine replacement therapy are useful and strongly recommended for patients with PAD.

Association between cardiometabolic index and atherosclerotic progression in patients with peripheral arterial disease.

BACKGROUND: Cardiometabolic index (CMI), calculated as a product of waist-to-height ratio and triglycerides-to-HDL cholesterol ratio, is a new index for discriminating diabetes mellitus. Patients with peripheral arterial disease (PAD) are prone to have other atherosclerotic diseases such as coronary artery disease and stroke. The purpose of this study was to clarify the relationships between CMI and indicators of atherosclerotic progression in patients with PAD. METHODS: The subjects were 63 outpatients with PAD. Relationships of CMI with variables related to atherosclerotic progression were investigated using multivariate linear regression analysis and analysis of covariance with adjustment for age, sex and histories of smoking and alcohol drinking. RESULTS: Log-transformed CMI was significantly correlated with mean intima-media thickness of the common carotid artery (IMT) (standardized regression coefficient: 0.350, p < 0.01) and % decrease in ankle-brachial systolic pressure index (ABI) after treadmill exercise (standardized regression coefficient: 0.365, p < 0.01). Mean IMT and % decrease in ABI by treadmill exercise were significantly higher (p < 0.01) in the group of the 3rd tertile for CMI than in the group of its 1st tertile (mean ± SE: mean IMT (mm), 0.94 ± 0.06 (1st tertile) vs. 0.94 ± 0.06 (2nd tertile) vs. 1.19 ± 0.06 (3rd tertile); % decrease in ABI, 14.1 ± 3.4 [1st tertile] vs. 26.0 ± 3.5 [2nd tertile] vs. 30.0 ± 3.5 [3rd tertile]). CONCLUSION: CMI was shown to be associated with the degrees of atherosclerosis in the common carotid artery and ischemia in leg arteries and is therefore a useful discriminator of atherosclerotic progression in patients with PAD.

[A case of bilateral extracranial carotid artery aneurysms caused by Takayasu's arteritis].

We describe here successful surgical treatment of a rare case of a rapidly enlarged aneurysm due to Takayasu's arteritis. A 22-year-old woman presented with a 1-month history of hoarseness and left neck pain. Contrast-enhanced computerized tomography showed an unruptured partially thrombosed aneurysm, and angiography revealed a large aneurysm of the common carotid artery. After hospitalization, the symptoms, interestingly, resolved spontaneously. While angiography at 2 weeks after admission showed the aneurysm to have reduced in size, 2 months later it showed the left common carotid artery aneurysm to be substantially enlarged in size and aneurysmal formation of the right external carotid artery. Surgical intervention was performed for the left common carotid artery aneurysm because rapid enlargement indicated the risk of aneurysmal rupture, and the thrombosis might cause embolic occlusion of the cerebral arteries. The left common carotid artery including enlarged aneurysm was trapped and anastomosed with a Gore-Tex graft (6-mm inner diameter) to left internal carotid artery. Histological examination of the arterial wall showed inflammatory change, destruction of the medial elastic fibers, and granulation with multinucleated giant cells. The postoperative course was uneventful, and no new vascular lesion was observed 3 years after operation. We demonstrated the bilateral extracranial carotid artery aneurysms caused by Takayasu's arteritis, which was the first case to be reported in the literature.

Intramuscular hemangioma in the right ventricle.

Intramuscular cardiac hemangiomas are extremely rare. We describe a 74-year-old man with a tumor occupying the apex of the right ventricle that was incidentally diagnosed by echocardiography. Computed tomography and coronary angiography showed that the tumor arose from the ventricular septum and that the feeding artery was a branch of the right coronary artery. The tumor was completely excised, and the postoperative course was uneventful. Histological examination revealed that the tumor was a cardiac hemangioma (intramuscular type). To our knowledge, this is only the second case report of an intramuscular cardiac hemangioma in the world literature.