A case of descending aortic dissection in a patient with unrepaired tetralogy of Fallot and pulmonary atresia.

The prognosis of tetralogy of Fallot with pulmonary atresia (TOF/PA) is mainly determined by the development of major aorto-pulmonary collateral arteries (MAPCAs) that provide pulmonary blood perfusion. TOF/PA can be managed conservatively until adulthood in patients with adequate, but not excessive perfusion via MAPCAs. To the best of our knowledge, this is the first report of a patient with unrepaired TOF/PA who eventually developed descending aortic dissection (AD), and survived with medical treatment. A 46-year-old woman was referred to our hospital by her local cardiologist with exertional dyspnea. A three-dimensional (3-D) computed tomography (CT) performed prior to presentation showed a dilated thoracic aorta, three well-developed MAPCAs, and a patent ductus arteriosus (PDA), whereas the 3-D CT performed at presentation revealed a descending AD with the entry site at the proximal part of the thoracic descending aorta, and neither the MAPCAs nor the PDA originated from the area of the AD. The patient was treated medically and was discharged thereafter. In this case, 3D-CT taken 9 months prior to the dissection showed no involvement of MAPCAs in the dissection area and was useful to make a decision of conservative therapy. Learning objective: Few systematic studies have addressed patients with tetralogy of Fallot with pulmonary atresia (TOF/PA) who survived more than 20 years due to optimal control of pulmonary blood flow depending on the development of major aorto-pulmonary collateral arteries (MAPCAs). We report a patient with unrepaired TOF/PA who developed descending aortic dissection (AD) in her forties. Three-dimensional computed tomography was useful for diagnosing and choosing a treatment plan by identifying the involvement of MAPCAs within the region of the AD.

Pharmacokinetics of Single and Multiple Oral Administration of a Self-emulsifying Formulation of Highly Purified Eicosapentaenoic Acid Ethyl Ester (MND-2119) Compared With the Nonself-emulsifying Formulation in Healthy Male Subjects.

MND-2119 is a self-emulsifying formulation of highly purified eicosapentaenoic acid ethyl ester (EPA-E) designed to be administered once daily due to improved absorption compared with the nonself-emulsifying formulation. In these studies, MND-2119 was administered to healthy adult males in single or multiple doses. In the single administration study, MND-2119 (0.5-4 g) was administered under fed and fasted conditions to evaluate MND-2119 pharmacokinetics and safety under these conditions. This study showed that Cmax and AUC0-72h of plasma EPA concentration after single administration were higher under fed conditions than under fasted conditions, for all doses. In the multiple administration study, subjects received either MND-2119 (0.5-4 g) immediately after breakfast or EPA-E (0.9 g) immediately after breakfast and dinner for 11 days to compare pharmacokinetics and safety of MND-2119 to EPA-E. In this study, the rate of rise in Cmin of the plasma EPA concentration with MND-2119 decreased from days 6 to 8 after administration and was thought to have reached a steady state on day 11. The mean Css,max of MND-2119 administered as 1 g once daily, and the mean Css,min and the mean AUCss,0-24h of MND-2119 administered as 2 g once daily were higher than those of EPA-E administered as 0.9 g twice daily. No safety-related issues occurred in either study. These results suggest that MND-2119 administered once daily may achieve equivalent or higher plasma EPA concentrations compared to the nonself-emulsifying formulation administered twice daily.

Long-term safety and efficacy of MND-2119 (self-emulsifying formulation of highly purified eicosapentaenoic acid ethyl ester) in patients with hypertriglyceridemia: Results from a multicenter, 52-week, open-label study.

BACKGROUND: In Japan, eicosapentaenoic acid ethyl ester (EPA-E) is administered twice-daily or three-times-daily for dyslipidemia. We have developed MND-2119, a novel self-emulsifying formulation of highly purified EPA-E which can be administered once-daily. OBJECTIVE: The objective of this study was to investigate the safety and efficacy of long-term administration of MND-2119 in hypertriglyceridemia patients. METHODS: In this multicenter, 52-week, open-label study, patients with high triglyceride (TG) (TG levels between ≥ 150 and < 500 mg/dL) undergoing lifestyle modification were randomized to MND-2119 2 g/day (n=61) or MND-2119 4 g/day (n=61). RESULTS: The incidence of adverse events in MND-2119 2 g/day and MND-2119 4 g/day was 70.5% and 62.3%, respectively, and the incidence of adverse drug reactions was 9.8% and 8.2%, respectively. There were no notable problems in the safety assessments of both treatment groups. By Week 4, TG levels had decreased from baseline in both groups, and the TG reducing effect continued up to Week 52 (mean percentage change from baseline in TG at Week 52 [two-sided 95% confidence interval]: MND-2119 2 g/day: -16.71% [-26.61, -6.81], MND-2119 4 g/day: -21.01% [-27.86, -14.16]). In both groups, plasma EPA concentration at Week 4 was maintained up until Week 52 and the plasma EPA concentration at Week 52 was 200.5 ± 54.7 µg/mL in MND-2119 2 g/day and 308.6 ± 98.6 µg/mL in MND-2119 4 g/day. CONCLUSION: Long-term administration of MND-2119 was not associated with any safety-related problems. TG levels decreased by Week 4, and the TG reducing effect continued up to Week 52.

Efficacy and safety of self-emulsifying formulation of highly purified eicosapentaenoic acid ethyl ester (MND-2119) versus highly purified eicosapentaenoic acid ethyl ester in patients with hypertriglyceridemia: Results from a 12-week randomized, double-blind, active-controlled, phase 3 study.

BACKGROUND: In Japan, eicosapentaenoic acid ethyl ester (EPA-E) is administered twice-daily or three-times-daily for dyslipidemia. We have developed MND-2119, a novel self-emulsifying formulation of highly purified EPA-E, which can be administered once-daily. OBJECTIVE: The objective of this study was to assess non-inferiority in the efficacy of MND-2119 in patients with hypertriglyceridemia compared with highly purified EPA-E. METHODS: In this multicenter, 12-week, double-blind study, patients with high triglyceride (TG levels between ≥ 150 and < 500 mg/dL) undergoing lifestyle modification were randomized to MND-2119 2 g/day (n=145), MND-2119 4 g/day (n=145), EPA-E 1.8 g/day (n=145) or EPA-E 2.7 g/day (n=145). The primary endpoint was percentage change in TG levels from baseline to end of treatment. RESULTS: MND-2119 2, 4 g/day and EPA-E 1.8, 2.7 g/day reduced TG levels from baseline by -10.09%, -15.51%, -9.30%, and -8.80%, respectively. The TG reduction rate of MND-2119 2 g/day was non-inferior to that of EPA-E 1.8 g/day (LS mean difference: -0.42, 95%CI: -5.76 to 4.91). Moreover, the TG reduction rate of MND-2119 4 g/day was superior to that of MND-2119 2 g/day (LS mean difference: -5.74, 95%CI: -10.59 to -0.89). There were no remarkable safety differences between MND-2119 2 g/day and EPA-E 1.8 g/day and between MND-2119 4 g/day and EPA-E 2.7 g/day. CONCLUSION: Non-inferiority of MND-2119 2 g/day to EPA-E 1.8 g/day for efficacy, and superiority of MND-2119 4 g/day over MND-2119 2 g/day for efficacy were verified. MND-2119 was safe and well tolerated.

Quantitative Volumetric Comparison of Direct Oral Anticoagulant and Vitamin K Antagonist Treatment for Pulmonary Thrombus Reduction During the Acute Phase in Symptomatic Patients.

BACKGROUND: Recent clinical trials' findings have revealed the therapeutic noninferiority of direct oral anticoagulant (DOAC) to standard therapy with vitamin K antagonist (VKA) in patients with pulmonary thromboembolism (PTE). However, few studies have quantitatively analyzed thrombus reduction in the pulmonary artery. METHODS: This observational study included 38 symptomatic PTE patients with stable hemodynamics. All patients received an intravenous heparin bolus followed by continual heparin injections immediately after the PTE diagnosis. The heparin was discontinued after edoxaban therapy began in the DOAC group (n = 22) or after the therapeutic range for the prothrombin time-international normalized ratio was achieved in the VKA group (n = 16). The thrombus volumes in the pulmonary arteries were quantitatively analyzed using contrast-enhanced computed tomography scans, and they were compared at baseline and at 2 weeks after admission. RESULTS: The pulmonary thrombus volumes declined in the VKA and DOAC groups from 7.9 to 4.2 cm3 (P = 0.048) and from 7.1 to 3.7 cm3 (P < 0.01), respectively, and the thrombus reduction rates did not differ significantly between the groups (-34% vs. -64%, respectively; P = 0.38). The fibrinogenolysis parameter changes during the14 days after admission were similar in both groups. Compared with the VKAgroup, the average hospital stay was 9days shorter in the DOAC group. There were no in-hospital deaths, and 1 case experienced major bleeding in the VKA group. CONCLUSIONS: In relation to pulmonary artery thrombus volume reduction, DOAC monotherapy for PTE may be comparable with standard therapy involving VKAs.

Effectiveness and safety of dabigatran versus warfarin in "real-world" Japanese patients with atrial fibrillation: A single-center observational study.

BACKGROUND: In "real-world" practice, anticoagulant therapy is indicated for patients whose clinical profiles are not addressed in randomized clinical trials. We assessed the effectiveness and safety of dabigatran versus warfarin in "real-world" Japanese patients with non-valvular atrial fibrillation (NVAF). METHODS: Among 613 NVAF patients who initiated dabigatran or warfarin therapy during the period between 2011 and 2013, 362 patients were included in the study after propensity score adjustment. The median follow-up period was 1.3 years. The effectiveness and safety outcomes were thromboembolism and major bleeding, respectively. RESULTS: The propensity-matched hazard ratios of thromboembolism and major bleeding with dabigatran were 1.03 (95% CI: 0.12-8.04, p=0.971) and 0.15 (95% CI: 0.01-0.90, p=0.037), respectively. CONCLUSIONS: The ability of dabigatran to prevent thromboembolism is comparable to that of warfarin; however, the major bleeding rate is lower with dabigatran in "real-world" NVAF patients.

Persistence of non-vitamin K antagonist oral anticoagulant use in Japanese patients with atrial fibrillation: A single-center observational study.

BACKGROUND: Non-vitamin K antagonist oral anticoagulants (NOACs) show a favorable balance between efficacy and safety compared with warfarin for patients with non-valvular atrial fibrillation (NVAF). In "real-world" practice, however, NOAC adherence and persistence among patients are not clear. The aim of this study is to evaluate NOAC and warfarin persistence in Japanese patients with NVAF who newly started these drugs. METHODS: We retrospectively studied 401 patients with NVAF who had newly started NOACs during the first 18 months after our hospital adopted their use (197 dabigatran, 107 rivaroxaban, 102 apixaban) and 200 patients with NVAF who had newly started warfarin during the same period. The endpoint was drug discontinuation for each drug. RESULTS: During the follow-up period (up to a maximum of 24 months), 113 (28%) patients who had newly started NOACs and 33 (17%) patients who had newly started warfarin discontinued the drug. The persistence rates of patients prescribed NOACs was lower than that of patients prescribed warfarin at 3, 6, and 12 months (85% versus 93%, 79% versus 88%, and 70% versus 82%, respectively). One-tenth of patients who had newly started NOACs discontinued the drug by their own decision. Drug adverse events, worsening renal dysfunction, and patient desire were the major causes of NOAC discontinuation. CONCLUSIONS: The rate of persistence of prescribed NOACs was significantly lower than that of warfarin in Japanese patients with NVAF.

Clinical outcome in Japanese elderly patients with non-valvular atrial fibrillation taking warfarin: a single-center observational study.

BACKGROUND: Although a lower target prothrombin time-international normalized ratio (PT-INR) with warfarin therapy is recommended in Japan for atrial fibrillation (AF) patients ≥70 years of age, few studies have provided supporting data. The current study aimed to evaluate the clinical outcome in elderly Japanese patients with non-valvular AF who were taking warfarin. METHODS: We conducted a cohort study of 845 consecutive non-valvular AF patients ≥70 years of age who were taking warfarin (median age, 74 years; 30.5% women) with a median follow-up period of 27 months (4-69 months). Of these patients, 29.7% had a history of stoke/transient ischemic attack (TIA), and 73.1% of the patients had a CHADS(2) score ≥2. The occurrence of thromboembolic events, including ischemic stroke, TIA and other systemic embolisms, and major bleeding events were validated through a review of medical records. RESULTS: The incidence of thromboembolic and major bleeding events were 3.8 and 2.1% per year, respectively. A higher incidence of both events was observed in patients with a CHADS(2) score ≥3. The multivariate analysis showed that prior stroke/TIA (odds ratio 1.7, 95% CI 1.0-2.7) and diabetes (odds ratio 1.7, 95% CI 1.0-2.8) were independent risks of thromoembolic events. A HAS-BLED score ≥3 represented a risk for major bleeding (hazard ratio 2.8, 95% CI 1.7-4.6). A PT-INR of 1.5-2.5 indicated a low incidence of thromboembolic and major bleeding events in patients with a CHADS(2) score ≥2. CONCLUSIONS: Our results demonstrate that a target PT-INR of 2.0 and a range of 1.5-2.5 may be safe for elderly Japanese patients with non-valvular AF.

A crucial role of activin A-mediated growth hormone suppression in mouse and human heart failure.

Infusion of bone marrow-derived mononuclear cells (BMMNC) has been reported to ameliorate cardiac dysfunction after acute myocardial infarction. In this study, we investigated whether infusion of BMMNC is also effective for non-ischemic heart failure model mice and the underlying mechanisms. Intravenous infusion of BMMNC showed transient cardioprotective effects on animal models with dilated cardiomyopathy (DCM) without their engraftment in heart, suggesting that BMMNC infusion improves cardiac function via humoral factors rather than their differentiation into cardiomyocytes. Using conditioned media from sorted BMMNC, we found that the cardioprotective effects were mediated by growth hormone (GH) secreted from myeloid (Gr-1(+)) cells and the effects was partially mediated by signal transducer and activator of transcription 3 in cardiomyocytes. On the other hand, the GH expression in Gr-1(+) cells was significantly downregulated in DCM mice compared with that in healthy control, suggesting that the environmental cue in heart failure might suppress the Gr-1(+) cells function. Activin A was upregulated in the serum of DCM models and induced downregulation of GH levels in Gr-1(+) cells and serum. Furthermore, humoral factors upregulated in heart failure including angiotensin II upregulated activin A in peripheral blood mononuclear cells (PBMNC) via activation of NFκB. Similarly, serum activin A levels were also significantly higher in DCM patients with heart failure than in healthy subjects and the GH levels in conditioned medium from PBMNC of DCM patients were lower than that in healthy subjects. Inhibition of activin A increased serum GH levels and improved cardiac function of DCM model mice. These results suggest that activin A causes heart failure by suppressing GH activity and that inhibition of activin A might become a novel strategy for the treatment of heart failure.

Increased P-selectin expression on platelets and decreased plasma thrombomodulin in Fontan patients.

BACKGROUND: Thromboembolic events account for significant morbidity and mortality after the Fontan procedure, but the underlying mechanisms remain unclear. P-selectin on platelets indicates platelet activation. Thrombomodulin (TM), a receptor for thrombin and a major anticoagulant proteoglycan on the endothelial membrane, reflects the anticoagulant activity of the endothelium. The present study investigated the hypothesis that the balance between platelet activation and endothelial biological function is impaired in Fontan patients. METHODS AND RESULTS: Platelet P-selectin as a marker of platelet activation, plasma TM levels and protein C activity, as markers of anticoagulant activity of the endothelium, and thrombin-antithrombin complex III (TAT) were examined in 43 Fontan patients. P-selectin levels on platelets (4.5 +/-1.4 vs 3.4 +/-0.4 mean fluorescence intensity, P<0.001) and TAT levels (80.2 +/-322.6 vs 1.9 +/-0.9 ng/ml, P<0.05) were significantly higher in Fontan patients than in control subjects. On the other hand, plasma TM levels (1.5 +/-0.8 vs 2.2 +/-0.3 FU/ml, P<0.01) and protein C activity (71 +/-35 vs 118 +/-25%, P<0.001) were significantly lower in Fontan patients compared with controls. These abnormalities were not seen in patients after other surgical procedures for congenital heart disease. CONCLUSIONS: Platelet activation is enhanced and endothelial function is impaired in patients after the Fontan procedure, which may partly explain the thromboembolic complications in Fontan patients.

Circulating platelet and neutrophil activation correlates with the clinical course of unstable angina.

Recent studies have suggested important roles of inflammation in the pathophysiology of unstable angina (UA). We investigated whether activation of the circulating platelets and neutrophils were implicated in inflammatory reactions associated with unstable angina Expressions of platelet P-selectin and neutrophil CD11b, and neutrophil-platelet aggregates were evaluated by flow cytometry in anticoagulated peripheral venous blood from 71 patients with UA and 22 patients with stable angina (SA). Expressions of platelet P-selectin and neutrophil CD11b, and neutrophil-platelet aggregates on the admission day were all significantly higher in 71 patients with UA than 22 with SA (median, mean fluorescence intensity [MFI]: 7.00 vs 4.51, P < 0.01, 64.68 vs 47.75, P = 0.0007; and % of 10 000 neutrophils: 7.84 vs 3.40, P = 0.0001, respectively). These three parameters in 43 patients with UA were significantly decreased (MFI: 4.23, P = 0.003, 50.82, P = 0.0003; and % of 10 000 neutrophils: 5.04, P = 0.0001, respectively) 7 days after the first measurement. These results indicate that circulating activated platelets and neutrophils are more strongly implicated in the acute phase of UA. These findings also suggest that thrombus formation after rupture of atherosclerotic plaques as well as plaque formation involves inflammatory reactions.

Increases in circulating T lymphocytes expressing HLA-DR and CD40 ligand in patients with dilated cardiomyopathy.

Inflammatory and immunological mechanisms are implicated in the development of idiopathic dilated cardiomyopathy (DCM). Since activated T lymphocytes express surface HLA-DR antigens, an increased level of these cells in the circulation could indicated an ongoing immune response. While the role of activated T lymphocytes in experimental myocarditis has been elucidated, the contribution of T lymphocyte activation in clinical DCM remains unclear. We therefore examined the role of T-cell activation in peripheral blood samples obtained from 10 patients with DCM (mean age, 49 +/- 12 years) and from 10 age-matched healthy controls. Citrated whole blood was mixed with fluorescein isothiocyanate- or phycoerythrin-conjugated specific monoclonal antibodies and analyzed using a fluorescence-activated cell sorter (FACS). The ratio (%) of histocompatibility leukocyte antigen (HLA)-DR positive cells in the FACS gated lymphocyte population was significantly higher in DCM patients than in controls (7.9% +/- 5.3% vs 2.0% +/- 0.9%; P < 0.01). The expression of CD40L on T cells determined as mean fluorescence intensity (MFI) was also significantly higher in DCM patients than in controls (3.6 +/- 2.1 vs 1.8 +/- 0.4 MFI; P < 0.05). Furthermore, the ratios of T cells expressing HLA-DR and serum brain natriuretic peptide (BNP) levels closely correlated (P = 0.0008). We showed that HLA-DR on peripheral T cells significantly correlated with serum BNP levels and that high CD40L expression on T cells was concomitant with increased BNP levels (P < 0.05). Therefore the magnitude of T-cell expression, such as increased expression of HLA-DR and CD40L, contributes to myocardial dysfunction in DCM.

High P-selectin expression and low CD36 occupancy on circulating platelets are strong predictors of restenosis after coronary stenting in patients with coronary artery disease.

Recent studies have shown that circulating platelets play an important role in the development of restenosis early after coronary stent implantation. We investigated P-selectin expression and CD36 blockade on platelets by flow cytometry in 48 consecutive patients who underwent coronary stenting. P-selectin expression was significantly higher 1 day after stenting in patients who had restenosis (n = 15) than in those who had no restenosis (n = 28), and the odds ratio for restenosis in patients with high P-selectin levels (MFI > 6.5) was 11.67 (P < 0.001) as compared with patients who had intermediate and low P-selectin levels. CD36 blockade was assessed with the use of two anti-CD36 antibodies, OKM5 and GS95 (our new anti-CD36 antibody), the binding of which indicates total CD36 amount and free CD36 unoccupied by lipid-related ligands, respectively. Binding of OKM5 to platelets was similar before and after stenting in both groups. CD36 blockade on platelets was seen 1 day after stenting in the non-restenosis group, and the odds ratio for restenosis in patients without CD36 blockade [GS95 binding ratio >0.8 as compared with binding before stenting] on day 1 was 28.60 (P < 0.001). P-selectin expression and unoccupied CD36 on platelets shortly after stenting may be strong predictors of post-stent restenosis.

Increased thrombogenesity in patients with cyanotic congenital heart disease.

BACKGROUND: The basic mechanisms of thromboembolism in cyanotic congenital heart disease (CCHD) have not been well clarified. P-selectin on the platelets reflects platelet activation. Thrombomodulin is a critical cofactor for thrombin-mediated activation of protein C and reflects the anticoagulant activity of the endothelium. The present study was performed to evaluate whether platelet activation exists in patients with CCHD. METHODS AND RESULTS: Platelet P-selectin as a marker of platelet activation, plasma thrombomodulin level and protein C activity as markers of anticoagulant activity of the endothelium and thrombin - antithrombin complex III (TAT) were examined in 35 patients with CCHD. Plasma thrombomodulin level (1.1+/-0.9 vs 2.2+/-0.3 FU/ml) and protein C activity (71.1+/-29.8 vs 117.8+/-24.8%) were significantly lower in patients with CCHD as compared with the control subjects. The levels of plasma TAT (255+/-811 vs 1.9+/-0.9 ng/ml) and P-selectin on platelets (6.3 +/-4.5 vs 3.3+/-0.3 mean fluorescence intensity) were significantly higher in the patients with CCHD than in the controls. Four of the CCHD patients who experienced thromboembolic events had elevated levels of platelet P-selectin (p=0.02) compared with CCHD patients without thromboembolic events. CONCLUSION: Platelet activation exists in patients with CCHD and it may play an important role in the thromboembolic events in CCHD.

Intracellular localization of glycoprotein VI in human platelets and its surface expression upon activation.

Glycoprotein (GP) VI is a major receptor for collagen and belongs to the immunoglobulin super family. Here, we examined the localization of GPVI in resting and activated human platelets by immunogold scanning and transmission electron microscopy and flow cytometry. Ultrastructural observation detected immunolabelling for GPVI that was distributed uniformly over the entire surface of resting platelets, and revealed that GPVI was also localized on both the membranes of the surface-connected open canalicular system (OCS) and alpha-granules. The OCS- and alpha-granule-associated GPVI pools were an estimated 35.4 +/- 3.2% (mean +/- standard deviation) of the total. Little GPVI labelling was observed in any part of GPVI-deficient platelets. A remarkable time-dependent increase in GPVI surface expression was found by flow cytometry when platelets were activated by collagen-related peptide (CRP) and convulxin. The GPVI-mediated activation of platelets by CRP or convulxin resulted in similar ultrastructural changes and an increased GPVI labelling density on the activated platelet surface, which was accompanied by a decreased interior expression. GPVI was also expressed on microparticles generated from activated platelets. Thus, our study demonstrates that platelets have internal pools of GPVI, and that GPVI is increasingly redistributed to the surface membrane and to microparticles during platelet activation.