[show abstract][hide abstract] ABSTRACT: PurposeThe purpose of this study was to evaluate the effect of treatment with an angiotensin-converting enzyme (ACE) inhibitor (Cilazapril)
for early hypertensive patients in terms of coronary blood flow reserve evaluated by13NH3-positron emission tomography (PET).
MethodsBefore and after 12 weeks of ACE inhibitor treatment,13NH3-PET with dipyridamole provocation test was performed, and definite myocardial perfusion and coronary flow reserve (CFR) were
ResultsCompared to our normal subjects previously reported (2.61±0.74), average coronary flow reserve was decreased (1.70±0.64 in
hypertensive patients), and improved after treatment (1.77±0.52), but not significantly. Of 12 patients, five (42%) showed
improved coronary flow reserve from 1.34 to 1.99 without a significant change in the resting flow. Only one patient (8%) showed
deterioration after the ACE inhibitor treatment. The coronary vascular resistance (CVR) after ACE inhibitor treatment of the
patients with CFR<2.0 decreased significantly compared with those with CFR≧2.0 (p<0.03).
ConclusionsThese results indicate that hypertensive patients at the early stage show decreased coronary flow reserve despite having normal
resting flow. Treatment with an ACE inhibitor (Cilazapril) for 12 weeks improved coronary flow reserve in 42% of our patients.
The CVR of the patients with CFR<2.0 showed improvement compared to those with CFR≧2.0.
This result indicates that an ACE inhibitor (e.g., Cilazapril) should be one of the choices for improving CFR if hypertensive
patients in early stage show signs of ischemia or diastolic dysfunction, which may be one of the sequels of reserve restriction.
Annals of Nuclear Medicine 04/2012; 14(5):353-360. · 1.41 Impact Factor
[show abstract][hide abstract] ABSTRACT: Coronary collateral circulation (CCC) is defined as an alternative blood-conveying circuit to the ischemic myocardium supplied by a jeopardized coronary artery. Accumulating evidence on CCC and its functional role has been derived from basic and clinical studies over several decades. Progress in molecular biology and genetic engineering has enabled us to elucidate the mechanisms of collateral growth on the basis of the development of new experimental models and methods for accurate assessment of CCC. These achievements in basic research have been promptly translated into the clinical setting. Interaction between basic and clinical sciences in the fascinating field of CCC will contribute to the establishment of innovative collateral-promoting therapy for severe coronary artery disease.
[show abstract][hide abstract] ABSTRACT: Low-dose antihypertensive drugs in combination are prescribed frequently in clinical practice. Combination treatment is superior to monotherapy with higher doses of each drug in terms of blood pressure reduction and side effects. However, it is unclear whether combination treatment provides additional prognostic benefit beyond the blood pressure lowering effects. We assessed the usefulness of the combined treatment of a renin-angiotensin system inhibitor (RASI) and a calcium channel blocker (CCB) for all cardiovascular events in the Japanese Coronary Artery Disease (JCAD) Study population. In the JCAD Study, which is an observational and non-randomized trial, 13,812 patients with angiographically shown narrowing >50% in ≥1 of 3 major coronary arteries were followed up for a mean of 2.7 years. The primary endpoint of the study was all cardiovascular events. In the present study, baseline covariates possibly influencing the event rate were adjusted between the different treatment groups. There was no statistically significant difference in the event rate between the RASI monotherapy and combined treatment groups, although Kaplan-Meier analysis showed a 23% (p = 0.0003) relative risk reduction with an RASI monotherapy compared with the control group. In conclusion, there may be no additional benefit beyond blood pressure lowering effects in the combination of an RASI and a CCB in patients with angiographically documented CAD.
Heart and Vessels 10/2010; 25(6):453-9. · 2.13 Impact Factor
[show abstract][hide abstract] ABSTRACT: There is a tremendous body of data concerning the coronary collateral circulation in both experimental animals and humans. The functional importance of a well-developed coronary collateral circulation has now been documented. The paradigm regarding the principal stimulus for coronary collateral growth has shifted from myocardial ischemia to increased shear stress at the site of pre-existing collateral arterioles. Numerous experimental and clinical studies have contributed to elucidation of the mechanisms of coronary collateral growth. Stimulation of coronary collateral growth is an alternative therapeutic approach to patients with intractable angina pectoris who are not indicated for percutaneous coronary intervention and/or coronary artery bypass grafting. Pharmacological and mechanical modulations accelerating coronary collateral growth have been challenged. Because it is conceivable that a well-developed coronary collateral circulation attenuates myocardial ischemia upon exercise, further research addressing coronary collateral growth is needed in both experimental models of myocardial ischemia and human coronary artery disease.
[show abstract][hide abstract] ABSTRACT: Calcium channel blockers (CCB) and statins are frequently prescribed for patients with coronary artery disease (CAD) complicated by hypertension and/or hypercholesterolemia. CCB have pleiotropic actions beyond their blood pressure-lowering effect, while statins have pleiotropic actions beyond their cholesterol-lowering effect. We assessed the hypothesis that combined treatment with CCB and statins has additional prognostic benefits resulting from potential additive or synergistic pleiotropic actions of both classes of drugs in the Japanese CAD (JCAD) study population. The JCAD study consisted of 13,812 patients with angiographically demonstrable significant coronary narrowing in at least 1 of 3 major coronary arteries who were followed-up for a mean of 2.7 years (follow-up rate, 88.4%). The primary endpoint of the present study was all cardiovascular events. We compared the event rate between patients receiving neither CCB nor statins and those receiving each drug alone or as a combination treatment using propensity score matching analysis. The rate of all events was 62.8 per 1,000 patient-years in the JCAD study. Kaplan-Meier analysis with the log-rank test showed no statistically significant difference in the event rate in each comparison. In conclusion, there may be no additional prognostic benefit beyond the blood-pressure-lowering and cholesterol-lowering effects in the combined treatment with CCB and statins for angiographically documented CAD patients.
International Heart Journal 01/2010; 51(5):299-302. · 1.23 Impact Factor
[show abstract][hide abstract] ABSTRACT: We have cloned a cDNA encoding rat neutrophil inducible nitric oxide synthase (iNOS). The amino acid sequence of the iNOS in the rat neutrophils was 95% identical to that in the mouse macrophages, and the difference between the two sequences was most likely the result of species variability. Moreover, the iNOS in the rat neutrophils was 99% identical in amino acid sequence to that in the rat hepatocytes and vascular smooth muscle cells (VSMC). Northern blot analysis of total RNA from both rat macrophages and neutrophils showed a single band above 4 kilo-nucleotides. These findings suggest that iNOS in rat neutrophils, macrophages, hepatocytes, and VSMC are almost identical in the primary structure.
[show abstract][hide abstract] ABSTRACT: Previously, we reported the benefit of 12 weeks of home oxygen therapy (HOT) in patients with central sleep apnea (CSA) and heart failure (HF). In the present study, we attempted to confirm the sustained efficacy of HOT in the long term treatment.
In the present study, 51 patients with CSA and HF (New York Heart Association (NYHA) functional classes II-III) were assigned to receive either nocturnal oxygen (HOT group n=26) or usual breathing (control group n=25) for 52 weeks. In the HOT group, greater reduction in apnea and hypopnea and greater increase in nocturnal oxygen saturation were observed. These changes were associated with greater improvement in the Specific Activity Scale (0.82 +/-1.17 vs -0.11 +/-0.73 Mets, P=0.009) in NYHA functional class (P=0.007) and in ejection fraction (5.45 +/-11.94 vs 1.28 +/-9.77%). There were no significant differences in the cardiac event rates; however, the later divergence favored the HOT group.
The 52-week HOT was well tolerated and the benefit observed in the 12-week trial was sustained over a prolonged period of time. HOT was considered to be a valuable non-pharmacological therapeutic addition for HF patients with CSA.
[show abstract][hide abstract] ABSTRACT: The efficacy and safety of abciximab were investigated in Japanese patients undergoing percutaneous coronary intervention (PCI) for acute myocardial infarction (MI) or unstable angina.
The 973 patients were randomized into 3 groups: the low-dose group (L group) received bolus injection of 0.20 mg/kg followed by 12-h infusion; the high-dose group (H group) received bolus injection of 0.25 mg/kg followed by 12-h infusion; the placebo group (P group) received bolus and infusion of placebo. The incidence of the primary endpoint (30-day post-PCI coronary events: death, MI or urgent revascularization) was 3.6%, 1.6%, and 4.1% in the P, L, and H groups, respectively, with no significant difference between the P and L groups (P=0.104) or between the P and H groups (P=0.772). The incidence of bleeding tended to increase in a dose-dependent manner.
No significant difference in the incidence of coronary events was found between the placebo and abciximab groups, so the efficacy of abciximab in preventing post-PCI coronary events in Japanese patients was not confirmed.
[show abstract][hide abstract] ABSTRACT: The S100A8/A9 complex is expressed in a subset of activated neutrophils and macrophages in acute inflammatory lesions associated with various diseases.
To investigate (a) whether serum S100A8/A9 levels are increased in patients with unstable angina (UA); and (b) whether S100A8/A9 expression is upregulated in coronary atherosclerotic plaques of patients with UA.
Serum S100A8/A9 levels in 39 patients with stable angina (SA) and 53 patients with UA were measured. In addition, the presence of the S100A8/A9 complex in directional coronary atherectomy specimens was studied immunohistochemically. Cell types which stain positive for S100A8/A9 were identified by immunodouble staining with neutrophils and macrophages.
Mean (SD) serum S100A8/A9 levels were significantly higher in patients with UA than in those with SA (3.25 (3.08) microg/ml vs 0.77 (0.31) microg/ml, p<0.05). In patients with UA, immunodouble staining clearly showed that the S100A8/A9 complex was expressed in infiltrated neutrophils and occasional macrophages. The S100A8/A9-positive area was significantly higher in UA than in SA (mean (SD) 18.3 (14.2)% vs 1.3 (2.4)%, respectively, p<0.001).
The S100A8/A9 complex may be involved in the inflammatory process of coronary atherosclerotic plaques in patients with UA.
[show abstract][hide abstract] ABSTRACT: There is increasing evidence that both obstructive and central sleep apnea contribute to the progression and prognosis in patients with chronic heart failure (CHF). In the main study of nocturnal home oxygen therapy (HOT) in patients with central sleep apnea because of CHF (CHF-HOT), significant improvements in oxygen desaturation index, apnea - hypopnea index, left ventricular ejection fraction, and specific activity scale were reported following 12 weeks of nocturnal HOT in these patients.
The present study is designed to further evaluate the clinical efficacy and cost - benefit of nocturnal HOT according to the results of a follow-up survey on changes in frequencies of hospitalization, emergency visits, and regular outpatient visits by 53 patients undergoing nocturnal HOT for more than 6 month periods. Medical costs were estimated from the DPC-MDC5 charge for hospitalization because of worsening heart failure (HF), and from the standard model case estimation for emergency and regular outpatient visits for HF. To reveal the time-saving benefit following nocturnal HOT, the influence on estimated days spent for hospital-care was also analyzed. The present study revealed significant reduction in frequencies and length of hospitalization (2.1 to 0.5 times/year, 38.7 to 34.6 days, medical cost: -2,686,267 yen), emergency visit (2.5 to 0.7 times/year, -15,984 yen), and regular outpatient visit (17.7 to 12.6 times/year, -6,324 yen) as compared with those before the induction of nocturnal HOT, which resulted in a total medical cost-reduction of 1,854,175 yen/patient/year, even with the additional charge for nocturnal HOT (854,400 yen/patient/year). Furthermore, nocturnal HOT produced a remarkable decline in estimated days spent for hospital-care (88.2 to 21.2 days/patient/year).
The present analysis calculated a remarkable cost-benefit (1,854,175 yen/patient/year) from the reduction in hospitalization and emergency visits, and also time-saving benefits from an increase in expected days free from hospital-care (67 days/patient/year).
[show abstract][hide abstract] ABSTRACT: Patients with certain types of glomerulonephritis often present with upper respiratory tract infection (URTI). In this in vitro study, we have examined several Japanese herbal medicines, Shosaiko-to (TJ-9), Saiboku-to (TJ-96), Sairei-to (TJ-114) and Ryokankyomi-singenin-to (TJ-119), which are occasionally used for collagen diseases, chronic inflammatory diseases or renal diseases. In these drugs, TJ-96 is used to treat bronchial asthma or URTI, which has anti-inflammatory effects. In this study, we demonstrate that TJ-9, TJ-96 or TJ-114 inhibits the proliferation of murine mesangial cells induced by platelet derived growth factor (PDGF) or tumour necrosis factor (TNF)-α. Quiescent mesangial cells were stimulated with 10 ng/mL of PDGF or 100 U/mL of TNF-α together with various concentrations of the medicines for 20 h. After incubation with 50μ/mL of TJ-9, TJ-96 or TJ-114, 3H-thymidine incorporation induced by PDGF was reduced to 26, 19 and 29% of the control; and 66, 56 and 75% on TNF-α stimulation, respectively. TJ-96 had a more intense inhibitory effect than TJ-9 or TJ-114. TJ-119 had no significant inhibitory effect at the same dose. Northern blot analysis for PDGF-B transcript after addition of TJ-96 revealed a 24% reduction in PDGF-B mRNA levels stimulated by recombinant PDGF-BB, suggesting inhibitory mechanisms of autocrine production of PDGF. No cytotoxic effect against mesangial cells in culture was observed up to a concentration of 100 μg/mL of TJ-9, TJ-96 or TJ-114 by lactic dehydrogenase release assay. By another cell viability assay, after medium with 50 μg/mL of TJ-96 was replaced with only PDGF-BB-containing medium, 3H-thymidine incorporation was found to exceed the control, suggesting rebound proliferation. the present findings suggest that administration of TJ-96 is beneficial for patients with mesangioproliferative glomerulonephritis accompanied by URTI, serving to regulate the effect on mesangial cell proliferation.
[show abstract][hide abstract] ABSTRACT: To determine the efficacy and safety of long-term bosentan monotherapy in Japanese patients with pulmonary arterial hypertension (PAH).
The present study was an extension to a 12-week open-label trial of bosentan in which 21 Japanese patients with PAH received bosentan, 125 mg twice daily. Of the 21 patients in the initial trial, 20 elected to participate in the long-term study and to continue to receive bosentan for up to 3 years.
The primary efficacy measure was comparison of World Health Organization (WHO) functional class for pulmonary arterial hypertension following long-term (> 2.5 years) therapy compared with baseline (prior to initiation of bosentan). Secondary outcomes included time from initiation of bosentan therapy to clinical worsening and safety assessments.
Bosentan treatment was continued for a median of 2.7 years (range 0.4-3.0 years); 12 patients received bosentan monotherapy for at least 2.5 years. Following long-term treatment, improvement of WHO functional class compared with baseline was observed in 9/12 patients (75.0%) and in 3/12 patients (25.0%) the functional class remained stable; no patient experienced a worsening of WHO functional class compared with baseline. Overall, long-term treatment with bosentan was well tolerated.
Long-term treatment with bosentan is well tolerated and is associated with sustained clinical improvement in Japanese patients with PAH. Bosentan, therefore, represents a valuable treatment option for Japanese patients with this devastating disease.
Current Medical Research and Opinion 03/2007; 23(2):395-400. · 2.26 Impact Factor
[show abstract][hide abstract] ABSTRACT: The effects of nasal oxygen (O(2)) supply at night using conventional home oxygen therapy (HOT) equipment on quality of life (QOL) and sleep-disordered breathing (SDB) were evaluated in patients with congestive heart failure (CHF). Nasal nocturnal O(2) therapy not only stabilizes SDB but also reduces sympathetic activity, and improves exercise capacity in patients with CHF. However, the effects of oxygen on the cardiac function and QOL of heart failure patients have not been fully elucidated.
Fifty-six patients with CHF (New York Heart Association class II - III, left ventricular ejection fraction (LVEF) <or=45%) and central sleep apnea (CSA) with Cheyne-Stokes respiration (CSR) were randomly assigned to receive either nocturnal O(2) (HOT group, n=25) or usual breathing (control group, n=31) for 12 weeks. Respiration, airflow and arterial oxygen levels were monitored with determination of apnea/hypopnea index (AHI) and oxygen desaturation index (ODI) during sleep. LV function was determined by radionuclide angiography or echocardiography. QOL was assessed by the Specific Activity Scale questionnaire. In the HOT group, nocturnal O(2) resulted in significant improvements in AHI (21.0 +/- 10.8 to 10.0+/-11.6 events/h, mean +/- SD, p<0.001), ODI (19.5 +/- 9.8 to 5.9 +/- 8.7 dips/h, p<0.001) and Specific Activity scale (4.0 +/- 1.2 to 5.0 +/- 1.5 Mets, p<0.001). LVEF also increased from baseline to the end of the study (34.7 +/- 10.4 to 38.2 +/- 13.6%, p=0.022).
In patients with stable CHF and CSR, HOT at night improves SDB, LV function and QOL, and thus is a valuable nonpharmacological option for the treatment of patients with CHF and CSR-CSA.
[show abstract][hide abstract] ABSTRACT: Oxidative stress, which is thought to be increased in subjects with various coronary risk factors, induces thioredoxin (TRX), a redox-active protein.
To determine whether oxidative stress is increased, serum concentrations of both TRX and alpha-tocopherol (vitamin E) were determined in 12 control subjects without any coronary risk factors (CONTROL), 6 current smokers (SMOKING), 19 hypertensive patients (HT), 7 hypercholesterolemic patients (HC) and 14 subjects with multiple risk factors (MULTIPLE). Patients with diabetes mellitus were not included. The serum TRX concentrations (mean +/- SD ng/ml) were significantly higher in SMOKING (41+/-10), HT (41+/-17), HC (48+/-15) and MULTIPLE (46+/-15) than in CONTROL (24+/-11). The serum alpha-tocopherol concentrations (mg/g lipids) were not significantly different among CONTROL (4.0+/-0.7), SMOKING (4.0+/-0.8), HT (4.1+/-0.6) and HC (4.2+/-0.6), although the concentration was significantly lower in MULTIPLE (3.3+/-0.7) than in any of the other study groups.
SMOKING, HT, HC and MULTIPLE had significantly higher serum TRX concentrations than CONTROL, suggesting increased oxidative stress. MULTIPLE had a lower serum concentration of antioxidant alpha-tocopherol than any of the other study groups, suggesting impaired or exhausted defense against chronic oxidative stress in the presence of the multiple risk factors.