Oral Iron Absorption of Ferric Citrate Hydrate and Hepcidin-25 in Hemodialysis Patients: A Prospective, Multicenter, Observational Riona-Oral Iron Absorption Trial.

Oral ferric citrate hydrate (FCH) is effective for iron deficiencies in hemodialysis patients; however, how iron balance in the body affects iron absorption in the intestinal tract remains unclear. This prospective observational study (Riona-Oral Iron Absorption Trial, R-OIAT, UMIN 000031406) was conducted at 42 hemodialysis centers in Japan, wherein 268 hemodialysis patients without inflammation were enrolled and treated with a fixed amount of FCH for 6 months. We assessed the predictive value of hepcidin-25 for iron absorption and iron shift between ferritin (FTN) and red blood cells (RBCs) following FCH therapy. Serum iron changes at 2 h (ΔFe2h) after FCH ingestion were evaluated as iron absorption. The primary outcome was the quantitative delineation of iron variables with respect to ΔFe2h, and the secondary outcome was the description of the predictors of the body's iron balance. Generalized estimating equations (GEEs) were used to identify the determinants of iron absorption during each phase of FCH treatment. ΔFe2h increased when hepcidin-25 and TSAT decreased (-0.459, -0.643 to -0.276, p = 0.000; -0.648, -1.099 to -0.197, p = 0.005, respectively) in GEEs. FTN increased when RBCs decreased (-1.392, -1.749 to -1.035, p = 0.000) and hepcidin-25 increased (0.297, 0.239 to 0.355, p = 0.000). Limiting erythropoiesis to maintain hemoglobin levels induces RBC reduction in hemodialysis patients, resulting in increased hepcidin-25 and FTN levels. Hepcidin-25 production may prompt an iron shift from RBC iron to FTN iron, inhibiting iron absorption even with continued FCH intake.

Impact of combined lipid lowering and blood pressure control on coronary plaque: myocardial ischemia treated by percutaneous coronary intervention and plaque regression by lipid lowering and blood pressure controlling assessed by intravascular ultrasonography (MILLION) study.

The aim of the study was to elucidate the aggressive reduction of both low-density lipoprotein cholesterol (LDL-C) and blood pressure (BP) reduced coronary atherosclerotic plaque volume compared with a standard treatment of LDL-C and BP in Japanese patients with coronary artery disease (CAD). This study is a prospective, randomized, and open-labelled with a blind-endpoint evaluation study. A total of 97 patients (81 men, mean age 62.0 ± 9.6) with CAD undergoing intravascular ultrasonography (IVUS)-guided percutaneous coronary intervention (PCI) were randomized, and 68 patients had IVUS examinations at baseline and at 18-24 months follow-up. Patients were randomly assigned to standard or aggressive strategies targeting LDL-C and a BP of 100 mg/dL and 140/90 mmHg vs. 70 mg/dL and 120/70 mmHg, respectively. The primary endpoint was the percent change in coronary plaque volume. Both standard and aggressive strategies succeeded to achieve target levels of LDL-C and BP; 74.9 ± 14.7 vs. 63.7 ± 11.9 mg/dL (NS) and 124.1 ± 9.4/75.8 ± 7.7 vs. 113.6 ± 9.6/65.8 ± 9.4 mmHg (systolic BP; NS, diastolic BP; p < 0.05), respectively. Both groups showed a significant reduction in the coronary plaque volume of -9.4 ± 10.7% and -8.7 ± 8.6% (NS) in standard and aggressive therapies, respectively. Both standard and aggressive intervention significantly regressed coronary plaque volume by the same degree, suggesting the importance of simultaneous reductions of LDL-C and BP for prevention of CAD.

Short- and long-term benefits of drug-eluting stents compared to bare metal stents even in treatment for large coronary arteries.

Although drug-eluting stents (DES) for percutaneous coronary intervention (PCI) have dramatically reduced the incidence of in-stent restenosis, their deployment for large-size coronary lesions is still controversial because of problems such as late in-stent thrombosis and late catch-up in DES. We aimed to evaluate the long-term outcome beyond 2 years of bare metal stents (BMS) as compared with DES in large vessels. Consecutive 228 patients who underwent PCI with large-size stents (>3.5 mm in diameter) in our hospital were enrolled in this study. The end points of this study are target lesion revascularization (TLR) and occurrence of major adverse cardiac events (MACE) for subject patients. We analyzed 183 patients (152 men, mean age 65.8 ± 10.5 years) whose outcome could be followed up for at least 2 years. At the first 8-month follow-up, clinically driven TLR rate was significantly higher in patients who received BMS than those who received DES (17.2 vs. 2.2 %, p < 0.05), although the rate of TLR was not different between the 2 groups beyond 8 months. Thus, overall rate of TLR was higher in BMS than in DES (22.7 vs. 5.4 %, p < 0.05). Under these conditions, the higher rate of TLR for BMS was observed in simple as well as complex lesions with or without diabetes, although there were no significant differences in MACE between BMS and DES. Multivariate analysis showed that BMS was an only independent factor of TLR at the 8 month follow-up period [p = 0.004, odds ratio 9.58, 95 % confidence interval (2.10-43.8)]. These results demonstrate that the rate of in-stent restenosis in large-size coronary lesions was transiently higher in the first 8 months for patients implanted with BMS compared with DES in which no in-stent thrombosis and TLR beyond 2 years were observed. We suggest using the DES even in large-size coronary lesions in terms of short- and long-term outcomes.

Impact of combined lipid lowering with blood pressure control on coronary plaque regression: rationale and design of MILLION study.

A line of epidemiological studies suggests that the accumulation of coronary risk factors promotes the progression of coronary atherosclerosis. Recent clinical studies showed that aggressive low-density lipoprotein (LDL) cholesterol-lowering therapy using statins could regress coronary atheroma and reduce major cardiovascular events. Additionally, therapy that controlled amlodipine-based blood pressure reduced major cardiovascular events in patients with hypertension compared with an atenolol-based regimen. An open-label randomized multicenter study is primarily planned to evaluate the changes in coronary atheroma volume using intravascular ultrasonography 18-24 months after intensive lowering of LDL-cholesterol and blood pressure compared with a standard therapy indicated by current guidelines in Japanese patients with coronary artery disease (CAD). The secondary endpoints include changes in serum lipid levels, inflammatory markers, glucose markers and blood pressure. In total, 100 subjects with CAD who are undergoing percutaneous coronary intervention will be tested. The MILLION study will provide new evidence and therapeutic standards for the prevention of CAD in Japanese patients by controlling both LDL-C levels and blood pressure.

[Laparoscopic adrenalectomy due to primary aldosteronism during pregnancy].

Primary aldosteronism (PA) during pregnancy is an extremely rare condition that may cause life threatening complications both for the mother and the fetus. A pregnant 31-year-old woman was referred to our hospital for the management of severe pregnancy hypertension at the beginning of her pregnancy. Her plasma aldosterone concentration (PAC) was markedly elevated (337 pg/ml), plasma rennin activity was suppressed (0.4 ng/ml/hr) and magnetic resonance imaging showed a 1.5 cm left adrenal tumor. PA due to an aldosterone producing-adenoma was diagnosed. Because of progressive uncontrollable hypertension and hypokalemia, a laproscopic adrenalectomy was performed at 24 weeks of gestation. The transabdominal approach was completed without any complication, resulting in normalization of PAC, easier management of blood pressure and improvement of hypokalemia. Because of severe pregnancy hypertension, cesarean operation was performed at 30 weeks of gestation and a girl weighing 1,235 g was delivered. The literature regarding PA during pregnancy was reviewed and the optimal timing of laparoscopic adrenalectomy during pregnancy and perioperative management were discussed.

Difference in coronary blood flow dynamics between patients with hypertension and those with hypertrophic cardiomyopathy.

We studied twelve patients with hypertensive left ventricular hypertrophy (LVH), 10 patients with hypertrophic cardiomyopathy (HCM) and 10 control subjects to examine the differences in coronary blood flow (CBF) dynamics between patients with hypertensive LVH and those with HCM. All subjects had normal coronary arteriograms. Measurements of CBF using Doppler Flo-Wire were performed at rest, and after infusions of acetylcholine and papaverine. The baseline CBF was significantly increased in both hypertensive LVH patients and HCM patients compared to that noted in control subjects (64.1+/-36.9, 80.0+/-38.1, 32.3+/-8.0 ml/min, respectively, p<0.01). Coronary flow reserve and endothelium-dependent vasodilatation were significantly lower in hypertensive LVH patients and HCM patients than in control subjects, but there was no significant difference between the hypertensive LVH and HCM patients themselves. In contrast, the diastolic/systolic velocity ratio at baseline was significantly lower in hypertensive LVH patients than in HCM patients (1.53+/-0.40, 6.31+/-7.50, p<0.05). Although CBF and coronary flow reserve correlated positively and negatively, respectively, with left ventricular mass index (r=0.51, -0.59, respectively), the diastolic/systolic velocity ratio at baseline did not show a significant correlation to left ventricular mass index. In conclusion, the diastolic/systolic velocity ratio differed between hypertensive LVH and HCM patients, independent of left ventricular mass. These results suggest that the difference of phasic pattern of CBF may be essential for coronary circulation in patients with hypertensive LVH and in those with HCM.

Impact of lesion morphology and associated procedures for left main coronary stenting on angiographic outcome after intervention: sub-analysis of Heart Research Group of Kanazawa, HERZ, Study.

Whether the lesion morphology and associated interventional procedures for the left main coronary artery disease (LMCA) could affect clinical outcome is still controversial. Therefore, we examined the impact of lesion morphology and associated procedures on clinical and angiographic outcomes of stenting for the LMCA. Among 7,660 patients with coronary intervention registered, we analyzed early angiographic results of 228 patients (179 men, mean age 69.4 years) concerned with LMCA lesions. In 121 out of 228 patients having long-term angiographic results, we examined the occurrence of major adverse coronary events (MACE) particularly in terms of the presence of acute coronary syndrome (ACS), the kind of stents, bear metal or drug eluting, the lesion morphology and associated procedures. Early angiographic success rate of LMCA stenting was 100 %, and clinical success rate was 94.3 %. During follow-up period for 3 years, MACE was observed in 17 patients. Under these conditions, multiple stenting (p < 0.01) and complicated procedures such as such as Y-stent, T-stent and crush stent (p < 0.01) were listed as risks for MACE, although there was no statistical difference in kinds of stent. Multivariate analysis demonstrated the significant disadvantage of complicated procedures using the bear metal stent on the occurrence of MACE (p < 0.01). These results demonstrate that the complicated procedures have great impact on clinical and angiographic outcomes after stenting for LMCA lesions, and suggest the simple procedure with a single stent for LMCA lesions in the present cohort. Whether the presence of ACS can affect the prognosis should further be sought.

Coronary artery stenting in a patient with factor XI deficiency.

Factor XI deficiency is a rare inherited coagulopathy first described in Ashkenazi Jews. In Japanese populations, factor XI deficiency is thought to be very rare. This disorder causes unique problems during percutaneous coronary intervention (PCI). During PCI, prevention of thrombosis is important and heparin is usually used for anticoagulation. However, care must also be taken to avoid serious complications of bleeding. These two situations are contradictory and anticoagulation with heparin might increase severe bleeding in patients with factor XI deficiency. An 84-year-old Japanese woman was admitted to our hospital for the treatment of worsening effort angina pectoris. A coronary angiography revealed severe stenotic lesions at the left main trunk (LMT) and the right coronary artery (RCA). While performing PCI of the LMT, 8,000 U of heparin were used and the patient underwent successful drug-eluting stent implantation. At this point, the patient's activated coagulation time was over 1,500 s and there was a marked decrease of factor XI activity (<3%: normal range 75-145%). After the diagnosis of factor XI deficiency, PCI for the RCA was scheduled without anticoagulation and fresh frozen plasma instead of dual antiplatelet therapy by aspirin and clopidogrel. Two drug-eluting stents were deployed and dilation using the kissing balloon technique was performed. The procedure was uneventful without stent thrombosis or distal embolization or bleeding. Because the literature on stenting for patients with factor XI deficiency is very limited, this case provides additional clinical information.

Rapid changes in plaque composition and morphology after intensive lipid lowering therapy: study with serial coronary CT angiography.

Although intensive lipid lowering by statins can enhance plaque stability, few data exist regarding how early statins change plaque composition and morphology in clinical setting. Therefore, to examine early changes in plaque composition and morphology by intensive lipid lowering with statins, we evaluate coronary plaques from acute coronary syndrome (ACS) before and 3 weeks after lipid lowering by coronary CT angiography. We enrolled 110 patients with suspected ACS and underwent coronary CT. We defined plaque as unstable when CT number of plaque< 50HU and remodeling index (lesion diameter/reference diameter) >1.10. Rosuvastatin (5 mg/day) or atorvastatin (20 mg/day) were introduced to reduce low density lipoprotein cholesterol (LDL-C). Then, CT was again performed by the same condition 3 weeks after lipid lowering therapy. Total 10 patients (8 men, mean age 72.0 years), in whom informed consent regarding serial CT examination was obtained, were analyzed. Among them, 4 patients who denied to have intensive lipid lowering were served as controls. In remaining 6 patients, LDL-C reduced from 129.5±26.9 mg/dl to 68.5±11.1 mg/dl after statin treatment. Under these conditions, CT number of the targeted plaque significantly increased from 16.0±15.9 to 50.8±35.0 HU (p<0.05) and remodeling index decreased from 1.22±0.11 to 1.11±0.06 (p<0.05), although these values substantially unchanged in controls. These results demonstrate that MDCT-determined plaque composition as well as volume could be changed within 3 weeks after intensive lipid lowering. This may explain acute effects of statins in treatment of acute coronary syndrome.

A case of acute myocardial infarction with repetitive stent thrombosis during emergent percutaneous coronary intervention. Transient decrease in antithrombin III activity and heparin resistance.

A 59-year-old woman was admitted to our hospital for the treatment of an acute anterior myocardial infarction. She had a history of uncontrolled diabetes mellitus, hypertension, hyperlipidemia, obesity, and smoking. Coronary angiography revealed 90% stenosis with spontaneous dissection in the proximal portion of the left anterior descending artery. At this time, heparin was initiated for the first time. Although direct stenting (Be-stent, 3.0-18 mm) was performed for the culprit lesion, coronary dissection occurred at the left main trunk and additional stenting (Multi Link ZETA stent 3.5-15mm) was performed for the left main trunk. Soon after stenting, repetitive stent thrombosis occurred. Aspiration of the thrombus using an aspiration catheter was ineffective and repetitive angioplasty and intraaortic balloon pumping were required. Although we used 17,000 units of unfractionated heparin during the intervention, the activated coagulation time (ACT) was not prolonged (157 seconds). In the coronary care unit, the ACT and activated partial prothrombin time (aPTT) were not prolonged despite the use of large amounts of heparin (69,000 units in 2 days). Protein-S, protein-C, and hepaplastin testing were within normal limits and heparin-platelet factor IV complex antibody was not detected. In the acute phase, a decrease in the antithrombin III activity (65%) was noted and with administration of argatroban, prolongation of the aPTT was achieved. In the chronic phase, the decrease in antithrombin III activity and heparin resistance had improved spontaneously. It is important to recognize the existence of transient decreases in antithrombin III activity in the acute phase of myocardial infarction.

Persistent left bundle branch block in a patient with dilated cardiomyopathy that improved with low dose carvedilol therapy.

A 43-year-old Japanese woman with dilated cardiomyopathy had complete left ventricular bundle branch block (CLBBB), which had persisted for at least two years. At the time of admission, the serum brain natriuretic peptide (BNP) concentration was 502 pg/mL (normal range, 0-18 pg/mL), the left ventricular diastolic dimension (LVDd) was 59 mm, the left ventricular systolic dimension (LVDs) was 54 mm, the %fractional shortening (FS) was 8%, and the left ventricular ejection fraction (LVEF) was 19.7% by echocardiography. Low dose carvedilol was initiated for the treatment of heart failure. Adverse effects, such as progression of cardiac conduction disturbances, did not occur after initiation of carvedilol therapy. About one year after initiation of carvedilol therapy, the CLBBB disappeared and a significant improvement in left ventricular function was noted. The LVDd was 44 mm, the LVDs was 30 mm, the %FS was 33%, and the LVEF was 61%, and the serum BNP concentration was decreased to 18.5 pg/mL. We describe a case in which low dose carvedilol was effective for treating both CLBBB and left ventricular function.