Differential Response to Heart Rate Reduction by Carvedilol in Heart Failure and Reduced Ejection Fraction Between Sinus Rhythm and Atrial Fibrillation　- Insight From J-CHF Study.

Background: Heart rate (HR) reduction by ß-blocker might not benefit patients with heart failure and reduced ejection fraction (HFrEF) with atrial fibrillation (AF). Methods and Results: The J-CHF study was a prospective randomized multicenter trial that assigned 360 HFrEF patients to a 2.5 mg/5 mg/20 mg target dose of carvedilol. Carvedilol was uptitrated over 8 weeks and then the dose was fixed. Of 321 patients available for analysis, AF was identified in 65 (20%). Using the median absolute change in HR at 32 weeks (∆HR), the subjects were further divided into group A (∆HR >-6 beats/min) and B (∆HR ≤-6 beats/min). Both in sinus rhythm (SR) and AF, baseline characteristics and achieved carvedilol dose were similar between groups A and B. In SR, the time-dependent change in left ventricular EF (LVEF) and LV end-diastolic dimension (LVEDD) over 56 weeks was more favorable in B compared with A (∆LVEF, P=0.036; ∆LVEDD, P=0.047), and ∆HR was independently associated with ∆LVEF (P=0.040). Group B had a lower rate of the primary endpoint, defined as a composite of death and hospitalization due to cardiovascular causes including acute decompensated HF at 3 years (P=0.002). ∆HR was an independent predictor of the primary endpoint (P=0.01), but this was not observed in AF. Conclusions: Response to the carvedilol HR reduction might differ in HFrEF between SR and AF.

Anemia Is Associated With Blunted Response to ß-Blocker Therapy Using Carvedilol　- Insights From Japanese Chronic Heart Failure (J-CHF) Study.

BACKGROUND: Anemia portends a poor clinical outcome in patients with chronic heart failure (CHF). However, its mechanism remains unknown. We sought to elucidate the effect of anemia on patients with HF with reduced ejection fraction (HFrEF) who receive carvedilol therapy.Methods and Results:J-CHF study was a prospective, randomized, multicenter trial that assigned 360 HFrEF patients to 2.5 mg/5 mg/20 mg carvedilol groups according to the target dose. At baseline 70 patients (19%) had anemia ([A]) defined as hemoglobin level (Hb) <13 g/dL (male) or <12 g/dL (female) and the remaining 290 did not ([N]). Allocated and achieved doses of carvedilol were similar. Left ventricular ejection fraction (LVEF) and plasma B-type natriuretic peptide (BNP) level significantly improved in both groups over 56 weeks, but they were smaller in [A] than in [N] (LVEF, P=0.046; BNP, P<0.0001 by ANOVA). Baseline Hb was an independent predictor of absolute change in LVEF (ß=0.13, P=0.047) and BNP (ß=-0.10, P=0.01). Presence of chronic kidney disease defined as estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2at baseline was not associated with differential response to carvedilol therapy. During 3.8±1.4 years follow-up, group [A] had a higher incidence of the composite endpoint of death, hospitalization for cardiovascular causes including HF compared with [N] (P=0.006). Baseline Hb was an independent predictor of the composite endpoint (hazard ratio 0.86, P=0.04), whereas baseline eGFR was not. CONCLUSIONS: Our data suggested that anemia was associated with a blunted response to carvedilol in HFrEF patients.

Presence of autoantibody directed against ß1-adrenergic receptors is associated with amelioration of cardiac function in response to carvedilol: Japanese Chronic Heart Failure (J-CHF) Study.

BACKGROUND: Autoantibody against ß1-adrenergic receptors (ß1-AAb) exerts agonist-like action inducing receptor uncoupling and myocardial damage. We attempted to determine the significance of ß1-AAb in chronic heart failure (CHF) patients who received carvedilol in a substudy of the Japanese Chronic Heart Failure study. METHODS AND RESULTS: In this prospective, randomized, multicenter trial, 117 patients were assigned to 2.5 mg, 5 mg, and 20 mg (n = 38, 36, and 43) carvedilol groups according to the target dose. ß1-AAb was positive in 51 patients (44%, P) and negative in 66 (56%, N). The percentage increase of left ventricular ejection fraction over 56 weeks (ΔLVEF) was larger in P than in N (P = .050) and in the high-titer group (H) than in the low-titer group (L; P = .04). Left ventricular (LV) volume decreased to a greater extent in H than in L over 56 weeks. ß1-AAb titer was significantly correlated with ΔLVEF and the percentage change of LV volume and was an independent predictor of them. No difference was seen in the composite end point (all-cause mortality and hospitalization for cardiovascular diseases or heart failure). However, in patients with dilated cardiomyopathy, it was more common in the 2.5 mg group than in the other groups in N, and it was similar among the 3 groups in P. CONCLUSIONS: Our data suggest that the presence of ß1-AAb is associated with favorable response to carvedilol in CHF.

Minimal dose for effective clinical outcome and predictive factors for responsiveness to carvedilol: Japanese chronic heart failure (J-CHF) study.

BACKGROUND: In chronic heart failure (CHF), it remains unclear whether the minimal dose of beta-blockade is related to survival benefits and which parameter predicts morbidity and mortality. We sought to determine the minimal dose related to survival benefits by comparing the efficacy and safety of three doses of carvedilol and the best predictive parameter for effective outcomes in Japanese patients with CHF. METHODS: In this prospective, randomized, stratified trial, 364 patients with mild to moderate CHF were assigned to a daily carvedilol dose of 2.5, 5, or 20mg, plus optimal standard therapy. FINDINGS: During the mean 3-year follow-up, resting heart rate (HR) and BNP were significantly reduced with dose-response relations in the early period but without dose-response relations in the late period. The LVEF and the LVDd were increased and decreased, respectively, without a dose-response relation. No significant difference was seen in the composite primary endpoint of all-cause mortality and hospitalization for cardiovascular diseases and heart failure. Multivariate analysis indicated early decreases in HR and BNP predicted long-term outcomes. However, adverse events increased dose-dependently. Among 237 polymorphisms in 87 heart failure-related genes, the osteopontin G-156 del genotype was associated with an event-free survival rate (Wilcoxon test, P=0.030). CONCLUSIONS: A low carvedilol dose is effective if the HR and/or plasma BNP has been reduced. Carvedilol therapy should be guided by reductions in HR and/or BNP, especially by initial HR reduction, but not only by its dose. OPN might be a surrogate genetic marker for long-term event-free survival.

The change in low-density lipoprotein cholesterol concentration is positively related to plasma docosahexaenoic acid but not eicosapentaenoic acid.

AIM: The Japan EPA Lipid Intervention Study (JELIS) reported a 19% reduction of the risk for coronary artery disease after long-term use of pure eicosapentaenoic acid (EPA) in Japanese patients with hypercholesterolemia. The variation in plasma fatty acid composition influenced the risk of coronary events. The aim of this study was to examine in JELIS participants the possible correlation of changes in plasma fatty acids with those of serum lipids. METHODS: The coefficient for the correlation between the absolute change in plasma fatty acid concentrations and the changes in serum lipids was calculated in 13,901 JELIS participants. RESULTS: Low-density lipoprotein (LDL) cholesterol exhibited a positive correlation with docosahexaenoic acid (DHA; r=0.117 in control group, r=0.155 in EPA group) and linoleic acid (r=0.139 in control group, r=0.177 in EPA group), but the correlation coefficients with EPA (r=0.097 in control group, r=-0.032 in EPA group) were less than 0.1. We distributed the patients into 9 groups according to tertiles of the change in EPA and DHA. The average absolute decrease of LDL cholesterol and L/H ratio in each group was significantly smaller (p<0.001) in the DHA-high tertile, but not in any EPA tertile. CONCLUSION: The changes in DHA, but not in EPA, showed a positive correlation with the changes in LDL-cholesterol.

Relationship between coronary artery disease and non-HDL-C, and effect of highly purified EPA on the risk of coronary artery disease in hypercholesterolemic patients treated with statins: sub-analysis of the Japan EPA Lipid Intervention Study (JELIS).

AIM: The present study examined the importance of reducing non-high-density lipoprotein cholesterol (non-HDL-C) for the primary prevention of the occurrence of coronary artery disease (CAD) in the JELIS, and the effects of EPA. METHODS: The patients were distributed into 4 subgroups using the lipid management goal for LDL-C recommended by the Japan Atherosclerosis Society guideline (2007) and the goal for non-HDL-C defined as 30 mg/dL higher than LDL-C: A) achieved both goals; B) achieved the LDL-C but not non-HDL-C goal; C) achieved the non-HDL-C but not LDL-C goal; and D) did not attain either goal. The incidences of CAD in the 4 subgroups were compared, and the effects of eicosapentaenoic acid (EPA) on the risk of CAD in these subgroups were examined. RESULTS: In the non-EPA group, the incidence of CAD in patients who did not achieve the goals for LDL-C or non-HDL-C was higher than in patients who achieved those goals. Patients in subgroups B, C, and D were at higher risk for CAD than those in subgroup A (B, HR 2.31; C, HR 1.90; D, HR 2.47). EPA reduced the risk of CAD by 38% in subgroups B, C, and D (p= 0.007). CONCLUSION: We reconfirmed non-HDL-C as a predictor of the risk for CAD and a residual risk marker of CAD after LDL-C-lowering therapy. EPA was useful to reduce the occurrence of CAD in patients who did not achieve the goals for LDL-C and/or non-HDL-C.

Relationships between plasma fatty acid composition and coronary artery disease.

AIM: The Japan EPA Lipid Intervention Study (JELIS) was the first prospective randomized clinical trial to demonstrate prevention of coronary events by pure eicosapentaenoic acid (EPA). The aim of this study was to examine the relationships between various plasma fatty acid concentrations and the risk of coronary events in JELIS participants. METHODS: In 15,534 participants, we calculated the hazard ratio for major coronary events (sudden cardiac death, fatal or nonfatal myocardial infarction, unstable angina pectoris, and angioplasty/stenting or coronary artery bypass grafting) relative to the on-treatment average level of plasma fatty acids with the Cox proportional hazard model. RESULTS: As a result of EPA intervention, the plasma EPA concentration increased, but the docosahexaenoic acid (DHA) concentration did not. The other fatty acids measured decreased slightly. The higher plasma level of EPA (hazard ratio=0.83, p=0.049, in all participants and hazard ratio=0.71, p=0.018, in the EPA intervention group), but not of DHA, was inversely associated with the risk of major coronary events. The associations between other fatty acids and the risk of major coronary events were not significant. In all JELIS participants, the risk of major coronary events was significantly decreased (20%) in the group with high (150 µg/mL or more) on-treatment plasma EPA concentration compared with that in the low (less than 87 µg/mL) group. CONCLUSION: The risk of coronary artery disease is influenced by variations in plasma fatty acid composition. Among n-3 polyunsaturated fatty acids, EPA and DHA exhibited differences in the correlation with the risk of major coronary events.

Doppler echocardiography in diastology: 35 years of Japanese contribution to its advancement and utility.

Echocardiography is one of the most important and clinically useful techniques in the assessment of diastolic function. Because of the prevalence of this technique, "diastology" and even the concept of diastolic heart failure have become familiar to researchers and physicians. We believe the first description by Kitabatake and his colleagues in 1982 of the use of Doppler technique to assess the transmitral flow velocity pattern in various cardiac diseases was the beginning of this development. Since then, a number of excellent works regarding echocardiographic assessment of diastolic function have emerged from Japan. Here, we review the Japanese contributions to the development of the use of Doppler echocardiography in diastology.

Preventive effects of eicosapentaenoic acid on coronary artery disease in patients with peripheral artery disease.

BACKGROUND: The JELIS trial examined the preventive effects of eicosapentaenoic acid (EPA) on coronary artery disease (CAD) in hypercholesterolemia. Previous investigators have reported that patients with peripheral artery disease (PAD) have a poor prognosis due to the potential risk for CAD. We conducted a subanalysis to examine whether the incidence of CAD was high in patients with PAD and whether EPA prevented the occurrence of CAD. METHODS AND RESULTS: Of 18,645 the Japan EPA lipid intervention study (JELIS) patients, 223 had PAD (control group; complicated (n=77), newly diagnosed (n=29), EPA group; complicated (n=96), newly diagnosed (n=21)). We analyzed the incidence of major coronary events (MCE) in the 2 groups. Cox proportional hazard ratio adjusted for baseline risk factor levels was used to test differences between the 2 groups. The incidence of MCE in the control group was significantly higher in patients complicated with PAD and in those newly diagnosed with PAD than in patients without PAD (complicated: hazard ratio 1.97, P=0.039; newly diagnosed: hazard ratio 2.88, P=0.030). As for patients with PAD, the EPA group had a significantly lower MCE hazard ratio than the control group (hazard ratio 0.44, 95% confidence interval 0.19-0.97, P=0.041). CONCLUSIONS: Subanalysis of the JELIS trial demonstrated that in patients with PAD the incidence of CAD was higher than in controls, and that EPA markedly reduced the occurrence of CAD in those patients.

Incremental effects of eicosapentaenoic acid on cardiovascular events in statin-treated patients with coronary artery disease.

BACKGROUND: Results from JELIS (Japan EPA Lipid Intervention Study) demonstrated the efficacy of pure eicosapentaenoic acid (EPA) in preventing coronary artery disease (CAD) in hypercholesterolemic patients under statin treatment. The present study examined in detail whether EPA is effective for the secondary prevention of CAD. METHODS AND RESULTS: Patients with established CAD and a total cholesterol level > or =250 mg/dl were observed with a mean follow-up of 4.6 years. They were randomly assigned to receive either 1,800 mg of EPA + statin (EPA group) or statin alone (control group). The incidence of major coronary events (MCE) were compared in the 2 groups. The incidence of MCE was significantly lower in the EPA group (8.7% vs 10.7%, adjusted hazard ratio =0.77, 95% confidence interval (CI) 0.63-0.96, P=0.017, number needed to treat (NNT) =49). Among 1,050 patients with prior myocardial infarction (MI), the incidence of MCE in the EPA group (15.0%) was significantly lower than that in the control group (20.1%, adjusted hazard ratio =0.73, 95%CI 0.54-0.98, P=0.033, NNT =19). CONCLUSIONS: EPA is effective for secondary prevention of CAD, especially in individuals with prior MI, and should be added to conventional treatment.

Suppressive effect of EPA on the incidence of coronary events in hypercholesterolemia with impaired glucose metabolism: Sub-analysis of the Japan EPA Lipid Intervention Study (JELIS).

BACKGROUND: JELIS was a large-scale clinical trial that investigated the effects of eicosapentaenoic acid (EPA) on coronary artery disease (CAD). In this paper, the data of patients registered in JELIS were analysed to compare the incidence of CAD between patients with impaired glucose metabolism (IGM) and normoglycemic (NG) patients. The effect of EPA on the incidence of CAD in patients with IGM was also assessed. METHODS: The 18,645 hypercholesterolemic patients registered in JELIS were divided into two groups. One group consisted of patients with IGM (n=4565), which included the patients who had diabetes mellitus and patients who had a fasting plasma glucose of 110mg/dL or higher, either at the time of registration or after 6 months. The other group consisted of NG patients (n=14,080). CAD incidence of the two groups over the average 4.6-year follow-up period was compared, and the effect of EPA was assessed. RESULTS: Compared to NG patients, IGM patients had a significantly higher CAD hazard ratio (1.71 in the non-EPA group and 1.63 in the EPA group). The treatment with EPA resulted in a 22% decrease in the CAD incidence (P=0.048) in IGM patients and an 18% decrease (P=0.062) in NG patients. CONCLUSIONS: It was found that the CAD risk in IGM patients is higher than in NG patients, and that highly purified EPA is very effective in decreasing the incidence of CAD among Japanese IGM patients, even though the intake of fish is high.

Prevalence of atrial fibrillation in the general population of Japan: an analysis based on periodic health examination.

BACKGROUND: The mortality and morbidity rates of various cardiovascular diseases differ between Western countries and Japan. The age- and gender-specific prevalence rate of atrial fibrillation (AF) in the general population of Japan was determined using the data from periodic health examinations in 2003. METHODS: Data of 630,138 subjects aged 40 years or more (47% were men and 34% were employees of companies and local governments) were collected from northern to southern Japan. The prevalence of diagnosed AF in each 10-year age group of both men and women was determined. Based on these prevalence rates and the Registry of Residents, the number of people having AF in Japan was estimated. RESULTS: The prevalence rate of AF increased as both male and female subjects aged, and it was 4.4% for men but only 2.2% for women aged 80 years or more (p<0.0001). As a whole, the AF prevalence of men was three times that of women (1.35 versus 0.43%, p<0.0001). There may be approximately 716,000 people (95% confidence interval (CI), 711,000-720,000) with AF in Japan, an overall prevalence of 0.56%. The number of people having AF was projected to be 1.034 (95% CI, 1.029-1.039) million, an overall prevalence of 1.09%, in 2050. CONCLUSIONS: The prevalence of AF increased in Japan as the population aged, as in Western countries. The overall prevalence of AF in Japan is approximately two-thirds of that in the USA. The projected increase in the number of people having AF is modest in Japan in 2050.

Effects of EPA on coronary artery disease in hypercholesterolemic patients with multiple risk factors: sub-analysis of primary prevention cases from the Japan EPA Lipid Intervention Study (JELIS).

BACKGROUND: Japan EPA Lipid Intervention Study (JELIS) was a large-scale clinical trial examining the effects of eicosapentaenoic acid (EPA) on coronary artery disease (CAD) in hypercholesterolemic patients. Herein, we focused on risk factors other than low-density lipoprotein cholesterol (LDL-C) to investigate the effects of EPA on CAD among JELIS primary prevention cases. METHODS: Hypercholesterolemic patients on statin therapy but without evidence of CAD (n=14,981) were randomly assigned to an EPA group (n=7503) or a control group (n=7478). The relationships between incident CAD, the number of CAD risk factors (hypercholesterolemia; obesity; high triglyceride (TG) or low high-density lipoprotein cholesterol (HDL-C); diabetes; and hypertension) and EPA treatment were investigated. RESULTS: For the control and EPA groups combined, a higher number of risk factors was directly associated with an increased incidence of CAD. Incidence was lower for the EPA group than for the control group regardless of the numbers of risk factors. Compared to patients with normal serum TG and HDL-C levels, those with abnormal levels (TG >or=150 mg/dL; HDL-C <40 mg/dL) had significantly higher CAD hazard ratio (HR: 1.71; 95% CI: 1.11-2.64; P=0.014). In this higher risk group, EPA treatment suppressed the risk of CAD by 53% (HR: 0.47; 95% CI: 0.23-0.98; P=0.043). CONCLUSIONS: Multiple risk factors besides cholesterol are associated with markedly increased incidence of CAD. High TG with low HDL-C represents a particularly potent risk factor. EPA was effective in reducing the incidence of CAD events for patients with this dyslipidemic pattern, suggesting that EPA may be especially beneficial in patients who with abnormal TG and HDL-C levels.

Reduction in the recurrence of stroke by eicosapentaenoic acid for hypercholesterolemic patients: subanalysis of the JELIS trial.

BACKGROUND AND PURPOSE: The JELIS trial examined the preventive effect of eicosapentaenoic acid (EPA) against coronary artery diseases. Hypercholesterolemic patients received statin only (no EPA group: n=9319) or statin with EPA (EPA group: n=9326) for around 5 years. EPA significantly suppressed the incidence of coronary events in previous analysis. Herein, we investigated the effects of EPA on the primary and secondary prevention of stroke. METHODS: We conducted a subanalysis of JELIS with respect to stroke incidence in the primary and secondary prevention subgroups defined as those without and with a prior history of stroke using Cox proportional hazard ratios, adjusted for baseline risk factor levels. RESULTS: As for primary prevention of stroke, this occurred in 114 (1.3%) of 8862 no EPA group and in 133 (1.5%) of 8841 EPA group. No statistically significant difference in total stroke incidence (Hazard Ratio, 1.08; 95% confidence interval, 0.95 to 1.22) was observed between the no EPA and the EPA groups. In the secondary prevention subgroup, stroke occurred in 48 (10.5%) of 457 no EPA group and in 33 (6.8%) of 485 EPA group, showing a 20% relative reduction in recurrent stroke in the EPA group (Hazard Ratio, 0.80; 95% confidence interval, 0.64 to 0.997). CONCLUSIONS: Administration of highly purified EPA appeared to reduce the risk of recurrent stroke in a Japanese population of hypercholesterolemic patients receiving low-dose statin therapy. Further research is needed to determine whether similar benefits are found in other populations with lower levels of fish intake. The trial is registered at ClinicalTrials.gov (number NCT00231738).

Prognosis and prognostic factors in patients with idiopathic dilated cardiomyopathy in Japan.

BACKGROUND: There have been few large-scale nationwide studies investigating both the prognosis and the prognostic factors of idiopathic dilated cardiomyopathy (IDC). A predictive score that can be used in clinical practice has not been established. METHODS AND RESULTS: A nationwide epidemiological study of the prognosis of IDC was conducted in 1999 among randomly selected hospitals in Japan, and 147 departments participated in the present 5-year follow-up survey. The vital status of 1,554 IDC patients was collected in 2004 using medical records and residence-based registers. The crude 5-year survival rate for those diagnosed in 1998 was 78.6%. Cox's regression model selected 5 independent predictors of mortality: male sex, higher age, higher New York Heart Association functional class, higher left ventricular diameter index, and lower left ventricular ejection fraction. A predictive score using these 5 variables effectively predicted prognosis; 5-year survival rates were 90.6% in patients with a score of 4 or less and 49.0% in patients with a score of 9 or 10. CONCLUSIONS: This nationwide survey revealed the present prognostic status of IDC in Japan and 5 independent predictors of prognosis that can be used in clinical practice as a predictive score.

Allograft inflammatory factor-1 augments macrophage phagocytotic activity and accelerates the progression of atherosclerosis in ApoE-/- mice.

Allograft inflammatory factor (AIF)-1, originally cloned from a rat heart allograft under chronic rejection, is induced in various inflammatory conditions including atherosclerosis. Using mouse AIF-1 transfected macrophages and AIF-1 transgenic (AIF-1 Tg) mice, we analyzed the influence of AIF-1 overexpression on macrophage phagocytosis and the development of atherosclerosis. The AIF-1 transfectants showed significantly increased phagocytosis of latex beads and E. coli BioParticles as well as incorporation of acetylated low-density lipoprotein (LDL) compared to those of vector controls. Concordant results were obtained with elicited peritoneal exudate cells from AIF-1 Tg mice. When AIF-1 Tg mice were crossbred with apolipoprotein E knockout mice (ApoE-/-), these AIF-1 Tg ApoE-/- mice developed significantly increased atherosclerotic lesions compared to ApoE-/- mice. These results suggest that enhanced AIF-1 expression leads to augmented incorporation of degenerated LDL by macrophages and promotes development of atherosclerotic vasculopathy.

Experimental study of the relationship between perfluoro-octyl bromide emulsion and norepinephrine release in reperfusion arrhythmia: isolated guinea pig heart model.

BACKGROUND: Perfluoro-octyl bromide (PFOB), one of the perfluorochemical oxygen transporters, improved postischemic cardiac dysfunctions. Also norepinephrine (NE) is one of the important inducible factors on reperfusion arrhythmias (ventricular fibrillation [VF]). We used these methods to evaluate the relationship between PFOB emulsion and NE release on reperfusion arrhythmias. MATERIALS AND METHODS: The perfusion of isolated guinea pig hearts was employed: each of four groups of 6-7 hearts were used with Krebs-Henseleit solution (KHS) as control, and KHS with 5%, 15%, or 30% PFOB emulsion. The hearts were perfused in a constant pressure Langendorff model, stabilized for 30 min, followed by 30 min preischemia, then 30 min ischemia and 45 min reperfusion at normothermia. RESULTS: PFOB emulsion dose-dependently limited VF and inhibited NE release in reperfusion. Only 30% PFOB emulsion showed the significant improvement of VF (p=0.05). In hemodynamic parameters, only 5% PFOB emulsion showed a significant decrease in reperfusion, but there was no difference in coronary flow rate (CFR). No differences among the four groups were demonstrated in cardiac oxygen metabolic parameters. CONCLUSIONS: It was most likely that a high concentration of PFOB emulsion attenuated reperfusion arrhythmia by decreasing NE release.

Percutaneous coronary intervention plus medical therapy reduces the incidence of acute coronary syndrome more effectively than initial medical therapy only among patients with low-risk coronary artery disease a randomized, comparative, multicenter study.

OBJECTIVES: This study sought to determine whether initial medical therapy (MT) only or percutaneous coronary intervention plus medical therapy (PCI+MT) is better for patients with low-risk stable coronary artery disease (CAD) indicated for intervention in Japan. BACKGROUND: Several multicenter studies have suggested that in the above patients, an initial management strategy of PCI+MT does not reduce the long-term risk of cardiovascular events more effectively than initial MT only. METHODS: We conducted a randomized comparative study (JSAP [Japanese Stable Angina Pectoris] study) in the previously mentioned patients. RESULTS: The patients were randomized to PCI+MT (n = 192) or initial MT only group (n = 192), and the patient characteristics were very similar in the 2 groups. During the 3.3-year follow-up, there was no significant difference in the cumulative death rate between PCI+MT (2.9%) and MT (3.9%). However, the cumulative risk of death plus acute coronary syndrome was significantly smaller in PCI+MT. CONCLUSIONS: In stable low-risk CAD, PCI+MT may improve long-term prognosis more effectively than MT.

Induction of c-fos mRNA expression by pure pressure overload in cultured cardiac myocytes.

Mechanical stress by pressure overload due to hypertension or valvular heart disease such as aortic valve stenosis induces cardiac hypertrophy. It has been well established that the mechanical stretch of cardiac myocytes in vitro induces hypertrophic responses such as the expression of immediate early response genes including c-fos. However, it remains uncertain whether the mechanical forces due to pure atmospheric pressure can induce similar responses in cardiac myocytes. We thus cultured rat neonatal cardiac myocytes in an atmospheric pressure chamber apparatus and determined the effects of pure pressure stress on c-fos gene expression. Pressures greater than 80 mmHg enhanced c-fos mRNA after 30 minutes. These results suggest that pure atmospheric pressure overload can also induce early hypertrophic responses in cardiac myocytes.