Effects of pitavastatin in Japanese patients with chronic heart failure: the Pitavastatin Heart Failure Study (PEARL Study).

BACKGROUND: Recent clinical trials using rosuvastatin, a hydrophilic statin, did not show beneficial effects on cardiovascular events in patients with heart failure. We examined the cardioprotective effects of pitavastatin, a lipophilic statin, on Japanese patients with chronic heart failure (CHF). METHODS AND RESULTS: A total of 574 Japanese patients with CHF were randomly assigned to the pitavastatin group (n=288) or the control group (n=286). There was no significant difference between the 2 groups for the primary outcome, which was a composite of cardiac death and hospitalization for worsening HF (adjusted hazard ratio (aHR): 0.922, 95% confidence interval (CI): 0.632-1.345, P=0.672). A strongly significant statistical interaction between the effect of pitavastatin and left ventricular ejection fraction (LVEF) was found (P=0.004). In patients with LVEF ≥30%, a significant reduction in the primary outcome (aHR: 0.525, 95% CI: 0.308-0.896, P=0.018) was observed in the pitavastatin group. Pitavastatin did not show any effects on the primary outcome (aHR: 1.582, 95% CI: 0.890-2.813, P=0.118) in the subgroup of patients with LVEF <30%. CONCLUSIONS: Pitavastatin did not reduce cardiac death or hospitalization for worsening HF in Japanese patients with CHF. (UMIN-ID: UMINC000000428).

Antiplatelet effect of 50-mg maintenance dose of clopidogrel compared to 200 mg ticlopidine: a preliminary study.

In the United States and Europe, patients with coronary stents are maintained on 75 mg clopidogrel. Because the maintenance dose of ticlopidine in patients with coronary stents is 100 mg twice daily in Japan and 250 mg twice daily in the United States and Europe, in Japanese patients a lower dose of clopidogrel may achieve an antiplatelet effect comparable to 200 mg ticlopidine. Platelet aggregation was evaluated in 104 consecutive patients on 50 mg clopidogrel plus aspirin (n = 54) and 200 mg ticlopidine plus aspirin (n = 50). Platelets were stimulated with adenosine diphosphate (5 and 20 mumol/l) and aggregation was assessed by optical aggregometry. There was no significant difference in platelet aggregation induced with 5 (37% +/- 11% vs 38% +/- 15%, not significant) and 20 mumol/l adenosine diphosphate (48% +/- 13% vs 51% +/- 12%, not significant) between 50 mg clopidogrel and 200 mg ticlopidine. In Japanese patients, there is the possibility that a maintenance dose of 50 mg clopidogrel on platelet inhibition is comparable to 200 mg ticlopidine.

The spindle pole body of the pathogenic yeast Cryptococcus neoformans: variation in morphology and positional relationship with the nucleolus and the bud in interphase cells.

The spindle pole body (SPB) in the interphase cell of the pathogenic yeast Cryptococcus neoformans was studied in detail by freeze-substitution and serial ultrathin sectioning electron microscopy. The SPB was located on the outer nuclear envelope and appeared either dumbbell- or bar shaped. The dumbbell-shaped SPBs were 228-365 nm long with amorphous spheres on each end, each sphere being 78-157 nm in diameter. The bar-shaped SPBs were 103-260 nm long and 32-113 nm thick. They consisted of filamentous materials. The dumbbell-shaped SPBs were more frequent (61%) than the bar-shaped SPBs. The bar-shaped SPBs may be regarded as dumbbell-shaped SPBs whose spherical parts became sufficiently small. There seemed to be no relationship between the SPB shape and the cell cycle stage of G1-G2, since both types of SPB appeared not only in unbudded cells but also in budded cells and their appearance seems to be random. It is not clear at present whether morphological changes between dumbbell- and bar shapes have any physiological function. The SPB tended to be localized away from the nucleolus (141 degrees +/- 44 degrees), but localized randomly to the bud (97 degrees +/- 50 degrees). The present study highlights the necessity of observing a large number of micrographs in three dimensions to describe accurately the ultrastructure of the SPB in yeast.

Prediction of functional recovery after revascularization using quantitative gated myocardial perfusion SPECT: a multi-center cohort study in Japan.

BACKGROUND: Prediction of left ventricular functional recovery is important after myocardial infarction. The impact of quantitative perfusion and motion analyses with gated single-photon emission computed tomography (SPECT) on predictive ability has not been clearly defined in multi-center studies. METHODS: A total of 252 patients with recent myocardial infarction (n = 74) and old myocardial infarction (n = 175) were registered from 25 institutions. All patients underwent resting gated SPECT using (99m)Tc-hexakis-2-methoxy-isobutyl isonitrile (MIBI) and repeated the study after revascularization after an average follow-up period of 132 +/- 81 days. Visual and quantitative assessment of perfusion and wall motion were performed in 5,040 segments. RESULTS: Non-gated segmental percent uptake and end-systolic (ES) percent uptake were good predictors of wall motion recovery and significantly differed between improved and non-improved groups (66 +/- 17% and 55 +/- 18%, p < 0.0001 for non-gated; 64 +/- 16% and 51 +/- 17% for ES percent uptake, p < 0.0001). The area under the curve of receiver operating characteristics curve for non-gated percent uptake, ES percent uptake, end-diastolic percent uptake and visual perfusion defect score was 0.70, 0.71, 0.61, and 0.56, respectively. Sensitivity and specificity of percent uptake were 68% and 64% for non-gated map and 80% and 52% for ES percent uptake map. An optimal threshold for predicting segmental improvement was 63% for non-gated and 52% for ES percent uptake values. CONCLUSION: Segmental (99m)Tc-MIBI uptake provided a useful predictor of wall motion improvement. Application of quantitative approach with non-gated and ES percent uptake enhanced predictive accuracy over visual analysis particularly in a multi-center study.

Valsartan Amlodipine Randomized Trial (VART): design, methods, and preliminary results.

Antihypertensive therapy has been well established to reduce hypertension related morbidity and mortality, but the optimal therapy for Japanese patients remains unknown. The Valsartan Amlodipine Randomized Trial (VART), a prospective randomized open-label trial, was designed to determine whether treatment with an angiotensin II type 1 receptor blocker (valsartan) or a calcium channel blocker (amlodipine) lowers cardiovascular disease events in essential hypertensives in Japan. Registration, randomization and data entry were performed over the Internet. The minimization method (to control for age, gender, blood pressure level and history) was used at random assignment to ensure that the background factors were equivalent between the groups at baseline. After the registration, patients were followed-up for cardiovascular events (primary endpoints), echocardiography, (123)I-metaiodobenzylguanidine (MIBG) imaging, laboratory tests and blood pressure for 3 years. Currently, 797 patients have been enrolled and assigned to two groups: a valsartan (n=399) and an amlodipine (n=398) group. At baseline, controlled factors (age, gender, blood pressure level, and left ventricular hypertrophy) and the proportions of patients with diabetes and hyperlipidemia were equally allocated. At 12 months, both drugs evenly and significantly lowered blood pressure to the target level (valsartan: 133/79 mmHg; amlodipine: 132/79 mmHg). In conclusion, by combining the data on cardiovascular events with the results of echocardiographic, radionuclide imaging, and blood/urine studies, the VART study will provide mechanistic insights into the clinical outcomes and treatment effects of the trial.

Critical roles of muscle-secreted angiogenic factors in therapeutic neovascularization.

The discovery of bone marrow-derived endothelial progenitors in the peripheral blood has promoted intensive studies on the potential of cell therapy for various human diseases. Accumulating evidence has suggested that implantation of bone marrow mononuclear cells effectively promotes neovascularization in ischemic tissues. It has also been reported that the implanted cells are incorporated not only into the newly formed vessels but also secrete angiogenic factors. However, the mechanism by which cell therapy improves tissue ischemia remains obscure. We enrolled 29 "no-option" patients with critical limb ischemia and treated ischemic limbs by implantation of peripheral mononuclear cells. Cell therapy using peripheral mononuclear cells was very effective for the treatment of limb ischemia, and its efficacy was associated with increases in the plasma levels of angiogenic factors, in particular interleukin-1beta (IL-1beta). We then examined an experimental model of limb ischemia using IL-1beta-deficient mice. Implantation of IL-1beta-deficient mononuclear cells improved tissue ischemia as efficiently as that of wild-type cells. Both wild-type and IL-1beta-deficient mononuclear cells increased expression of IL-1beta and thus induced angiogenic factors in muscle cells of ischemic limbs to a similar extent. In contrast, inability of muscle cells to secrete IL-1beta markedly reduces induction of angiogenic factors and impairs neovascularization by cell implantation. Implanted cells do not secret angiogenic factors sufficient for neovascularization but, instead, stimulate muscle cells to produce angiogenic factors, thereby promoting neovascularization in ischemic tissues. Further studies will allow us to develop more effective treatments for ischemic vascular disease.

Effect of mental stress on coronary flow velocity reserve in healthy men.

The effect of mental stress on coronary flow velocity reserve (CFVR) was examined in healthy men using transthoracic Doppler echocardiography. In the mental stress group (n = 31), CFVR was significantly reduced at 15 (to 3.3 +/- 0.8, p <0.001) and 30 (to 3.7 +/- 0.8, p <0.01) minutes after mental stress testing, compared with before mental stress (4.3 +/- 0.9), whereas it did not change in each of 3 measurements in control subjects (n = 10). Mental stress impaired coronary circulation even after a certain interval after the stress.

The spindle pole body of the pathogenic yeast Exophiala dermatitidis: variation in morphology and positional relationship to the nucleolus and the bud in interphase cells.

The spindle pole body (SPB) in the interphase cell of the pathogenic yeast Exophiala dermatitidis was studied in detail. The SPB was located on the outer nuclear envelope and was 342 +/- 86 nm long in a haploid strain. It consisted of two disk elements that measured 151 +/- 43 nm in diameter and 103 +/- 17 nm in thickness, connected by a rod-shaped midpiece that measured 56 +/- 20 nm in length and 37 +/- 9 nm in diameter. There were considerable variations in size and morphology of interphase SPB. Some disk elements appeared spherical but others were more flattened, and there was variation in electron density. A few SPBs did not have the midpiece. The SPB of a diploid strain was 486 +/- 118 nm long, thus significantly bigger than that of the haploid strain. The SPB tended to be localized away from the nucleolus (110 +/- 48 degrees), but close to the bud (78 +/- 45 degrees). The present study highlights the necessity of observing a large number of micrographs in three-dimensions to describe accurately the ultrastructure of the SPB in yeast.

Rationale and design of a study to evaluate effects of pitavastatin on Japanese patients with chronic heart failure: the pitavastatin heart failure study (PEARL study).

BACKGROUND: HMG-CoA reductase inhibitors (statins) are known to have pleiotropic effects in addition to their lipid-lowering effect. Many studies have suggested cardioprotective effects of statins, however, recent large-scale clinical trials using rosuvastatin, a hydrophilic statin, have failed to show beneficial effects on cardiovascular events in patients with severe heart failure. We have designed the study to evaluate the effects of pitavastatin, a lipophilic statin, on Japanese patients with mild to moderate heart failure. METHODS AND RESULTS: Five hundred seventy-seven patients with chronic heart failure were enrolled. We used a prospective, randomized, open-label, and blinded-endpoint evaluation (PROBE) design. Patients aged 20-79 years old with symptomatic (NYHA functional class II or III) heart failure and a left ventricular ejection fraction of ≤ 45% were randomly allocated to either receive pitavastatin (2mg/day) or not in addition to conventional therapy for heart failure by using the minimization method. Follow-up will be continued until March 2011. The primary endpoint is a composite of cardiac death and hospitalization for worsening heart failure. CONCLUSIONS: The PEARL study will provide important data on the role of pitavastatin in the treatment of Japanese patients with mildly symptomatic heart failure (UMIN-ID: UMINC000000428).

Determination of the survival rate in patients with congestive heart failure stratified by ¹²³I-MIBG imaging: a meta-analysis from the studies performed in Japan.

BACKGROUND: The goals of this meta-analysis were to determine survival rates in patients with heart failure (HF) assessed by ¹²³I-MIBG imaging results using recently published studies and to determine the prognostic value of ¹²³I-MIBG imaging. METHODS: We reviewed published cohort studies carried out in Japan that compared the prognosis of patients with their ¹²³I-MIBG activity quantified as late heart-to-mediastinum ratio (H/M) or washout rate by performing a PubMed search for articles in English up to December 2006. Studies were selected if they analyzed a clearly defined lethal outcome (cardiovascular death) using life tables to estimate the odds ratio at 24 months after enrollment. RESULTS: Of 158 articles related to cardiac ¹²³I-MIBG, seven referred to studies that met the inclusion criteria: 5 evaluated H/M via ¹²³I-MIBG in a total of 866 patients and 4 calculated washout rate in a total of 491 patients. A low H/M indicated a high risk of cardiac death: pooled odds ratio, 5.2; 95% confidence interval (CI) of 3.1-5.7. A high washout was also associated with lethal events with a pooled odds ratio of 2.8 (CI: 1.6-5.0). The association between washout and cardiac death was heterogeneous (Chi-square = 11.0, P < 0.02), whereas that between late H/M and fatal events was homogeneous (Chi-square = 2.3, P = no significance). CONCLUSION: This meta-analysis of published studies of ¹²³I-MIBG studies conducted in Japan indicated that both a decreased cardiac ¹²³I-MIBG activity (H/M) and an increased washout rate are indicative of a poor prognosis in patients with chronic heart failure.

Effects of valsartan and amlodipine on cardiorenal protection in Japanese hypertensive patients: the Valsartan Amlodipine Randomized Trial.

The Valsartan Amlodipine Randomized Trial, a multicenter, prospective, randomized, open-labeled, blinded-end point trial, was designed to compare the beneficial effects of the angiotensin II receptor blocker valsartan and the calcium channel blocker amlodipine on cardiovascular events in Japanese essential hypertensive patients. The primary end point was a composite of all-cause death, sudden death, cerebrovascular death, cardiac events, vascular events and renal events. The secondary endpoints were effects on left ventricular hypertrophy, cardiac sympathetic nerve activity and renal function. A total of 1021 patients were enrolled in the present trial. The mean follow-up period was 3.4 years. There were no significant differences in blood pressure (BP) levels between the valsartan group and the amlodipine group throughout the trial. There was no significant difference in the primary endpoint between the two groups (hazard ratio: 1.0, P = 0.843). No difference in any event category of the primary endpoint was noted for either group. However, we observed a significant reduction of left ventricular mass index, as determined by echocardiography, in the valsartan group compared with the amlodipine group. We also observed a significant decrease in cardiac sympathetic nerve activity in the valsartan group but not in the amlodipine group. Moreover, there was a significant reduction in the urinary albumin to creatinine ratio in the valsartan group but not in the amlodipine group. Therefore, although BP levels were well controlled and remained equal in the two groups, valsartan had more protective effects on the heart and kidney than amlodipine in Japanese hypertensive patients.

Long-term outcome of therapeutic neovascularization using peripheral blood mononuclear cells for limb ischemia.

BACKGROUND: Injection of bone marrow mononuclear cells has been reported to promote neovascularization of ischemic tissues effectively. We found that peripheral blood mononuclear cells were as efficient as bone marrow mononuclear cells for the treatment of limb ischemia in animals and showed that this treatment was feasible and safe in no-option patients with limb ischemia. However, the long-term outcome of such therapy has not been investigated. METHODS AND RESULTS: We retrospectively analyzed the data for 42 patients who were treated between July 2002 and December 2005 by using the log-rank test, the Kaplan-Meier method, and the Cox proportional hazard model. Improvement of ischemic symptoms was observed in 60% to 70% of the patients. The annual rate of major amputation was decreased markedly by treatment. Improvement of ischemic symptoms was less marked in arteriosclerosis obliterans (ASO) patients on dialysis compared with nonhemodialysis ASO or thromboangiitis obliterans patients. Indeed, the survival rate of these patients was lower than that of nonhemodialysis ASO or thromboangiitis obliterans patients. Major adverse events such as death, major amputation, and cardiovascular events occurred mostly in ASO patients, and most of them were on dialysis. There was no significant difference in the cardiovascular event-free rate between responders and nonresponders. The survival rate of younger responders was better than that of nonresponders. CONCLUSIONS: Although this study was not placebo-controlled and these initial results were from a retrospective analysis, injection of peripheral blood mononuclear cells might be safe and potentially effective for the treatment of limb ischemia, but caution is needed when managing ASO patients on dialysis.

Quantitative gated single-photon emission computed tomography with (99m)Tc sestamibi predicts major cardiac events in elderly patients with known or suspected coronary artery disease: the QGS-Prognostic Value in the Elderly (Q-PROVE) Study.

BACKGROUND: Although electrocardiogram-gated single-photon emission computed tomography (SPECT) may be useful in risk stratification of elderly patients with coronary artery disease (CAD), few studies have prospectively evaluated its prognostic value in this patient population. METHODS AND RESULTS: A total of 175 patients aged 75 years or more with known or suspected CAD were prospectively evaluated by stress gated SPECT using a 20-segment model and an automatic functional analysis. Patients with acute coronary syndrome within the previous 3 months, and those who underwent coronary revascularization within 3 months after the SPECT study were excluded. Outcome assessment included prespecified cardiac events and noncardiac deaths. During a mean follow-up of 3.4 years, there were 18 cardiac events: 2 cardiac deaths, 1 nonfatal myocardial infarction, 3 coronary artery bypass grafting, 5 percutaneous coronary interventions, 1 unstable angina, 4 heart failures, and 2 malignant arrhythmias. Kaplan-Meier survival estimation indicated an event-free survival rate of 98.1% at 3 years in patients without myocardial ischemia, but 79.9% in those with ischemia as documented by gated SPECT (p=0.0001). Multivariate analysis using the Cox proportional hazard model demonstrated that stress-induced myocardial ischemia was the only independent predictor for subsequent cardiac events (p<0.01). CONCLUSIONS: Stress gated SPECT predicts cardiac events in patients aged 75 years or more with known or suspected CAD and may have a role in risk stratification of this patient population.

Feasibility and safety of granulocyte colony-stimulating factor treatment in patients with acute myocardial infarction.

BACKGROUND: This study examined feasibility and safety of granulocyte colony-stimulating factor (G-CSF) treatment for patients with acute myocardial infarction (AMI). METHODS: Forty patients with AMI related with the left anterior descending coronary artery, who underwent successful percutaneous coronary intervention (PCI), were randomized into G-CSF group (n=18) or Control group (n=22). G-CSF treatment was started within 24 h after PCI. 99mTc-tetrofosmin single-photon emission computed tomography (SPECT) was performed at 4 days and 6 months after AMI. SPECT data was analyzed for LV end-diastolic volume (LVEDV), LV end-systolic volume (LVESV), LV ejection fraction (LVEF) and myocardial perfusion. RESULTS: LVEF at 6 months was significantly better than that at 4 days in G-CSF group (p=0.013), but not changed in Control group (p=0.245). Although no significant difference was observed for LVEDV between the two groups, LVESV tended to be decreased only in G-CSF group. In G-CSF group, defect score (DS) was significantly decreased from 4 days to 6 months after AMI. Restenosis rate at 6 months after AMI was not significantly different between the two groups. CONCLUSIONS: G-CSF treatment for patients with AMI was effective and did not have any clinical and angiographic adverse effects.