Takao Yamauchi

Statin treatment for coronary artery plaque composition based on intravascular ultrasound radiofrequency data analysis

BACKGROUND Systemic therapy with statin has been shown to lower the risk of coronary events; however, the in vivo effects of statin therapy on plaque volume and composition are less understood. METHODS We conducted a prospective, open-labeled, randomized, multicenter study in 11 centers in Japan. A total of 164 patients were randomized to receive either 4 mg/d of pitavastatin (intensive lipid-lowering therapy) or 20 mg/d of pravastatin (moderate lipid-lowering therapy). Analyzable intravascular ultrasound data were obtained for 119 patients at baseline and at 8-month follow-up. The primary end point was the difference of volume changes in each of the 4 main plaque components (fibrosis, fibrofatty, calcium, and necrosis), assessed by virtual histology intravascular ultrasound, between the 2 groups. RESULTS The mean low-density lipoprotein cholesterol level at follow-up was significantly lower in the pitavastatin than in the pravastatin group (74 vs 95 mg/dL, P < .0001). During the 8-month follow-up period, statin therapy reduced the absolute and relative amount of fibrofatty component (pitavastatin: from 1.09 to 0.81 mm(3)/mm, P = .001; pravastatin: from 1.05 to 0.83 mm(3)/mm, P = .0008) and increased in the amount of calcium (pitavastatin: from 0.42 to 0.55 mm(3)/mm, P < .0001; pravastatin: from 0.44 to 0.55 mm(3)/mm, P = .005), whereas volume changes in both plaque components were not statistically different between the 2 groups. CONCLUSIONS Both pitavastatin and pravastatin altered coronary artery plaque composition by significantly decreasing the fibrofatty plaque component and increasing the calcified plaque component.

Sudden Cardiac Death and Left Ventricular Ejection Fraction During Long-Term Follow-up After Acute Myocardial Infarction in the Primary Percutaneous Coronary Intervention Era. Results from the HIJAMI-II Registry

Objective: To determine the incidence of sudden cardiac death (SCD) according to left ventricular ejection fraction (LVEF) in survivors of myocardial infarction (MI) in the primary percutaneous coronary intervention (PCI) era. Design: A multicentre observational prospective registered cohort study. Setting: 18 medical centres in Japan. Patients: 4122 consecutive patients (mean age 66 (SD 12) years, 73.7% male) with acute MI, who were discharged alive. Main outcome measures: The primary end-point was SCD, and a secondary end-point was death from any cause. Results: Patients were categorised into three groups: LVEF >40% (n = 3416), LVEF ⩽40% and >30% (n = 507) and LVEF ⩽30% (n = 199). Among all patients, 77.8% received PCI and 3.7% received coronary artery bypass graft surgery. During an average follow-up of 4.1 years, SCD was 1.2% and mortality was 13.1%. Patients with LVEF ⩽30% and LVEF ⩽40% and >30% were at increased risk for SCD (HR 5.99, 95% CI 2.73 to 13.14, p<0.001, HR 3.37, 95% CI 1.74 to 6.50, p<0.001, respectively), and mortality (HR 3.85, 95% CI 2.96 to 5.00, p<0.001, HR 2.06, 95% CI 1.66 to 2.57, p<0.001, respectively), compared to patients with LVEF >40%. Kaplan-Meier estimates of SCD in patients with LVEF ⩽30% were 2.9%, 5.1% and 5.1% at 1, 3 and 5 years, respectively. Conclusion: There is a low incidence of SCD in survivors of MI in the primary PCI era, although LVEF is a predictor of increased risk for SCD.

Effects of serum n-3 to n-6 polyunsaturated fatty acids ratios on coronary atherosclerosis in statin-treated patients with coronary artery disease.

A low ratio of n-3 to n-6 polyunsaturated fatty acids has been associated with cardiovascular events. However, the effects of this ratio on coronary atherosclerosis have not been fully examined. The purpose of the present study was to evaluate the correlations between the n-3 to n-6 polyunsaturated fatty acid ratio and coronary atherosclerosis. Coronary atherosclerosis in nonculprit lesions in the percutaneous coronary intervention vessel was evaluated using virtual histology intravascular ultrasound in 101 patients at the time of percutaneous coronary intervention and 8 months after statin therapy. Forty-six patients (46%) showed atheroma progression and the remaining 55 patients (54%) showed atheroma regression at 8-month follow-up. Significant negative correlations were observed between percentage change in plaque volume and change in the eicosapentaenoic acid (EPA)/arachidonic acid (AA) ratio (r = -0.190, p = 0.05), docosahexaenoic acid (DHA)/AA ratio (r = -0.231, p = 0.02), and EPA+DHA/AA ratio (r = -0.240, p = 0.02). Furthermore, percentage change in the fibrous component volume was negatively and significantly correlated with change in the EPA/AA ratio (r = -0.206, p = 0.04) and EPA+DHA/AA ratio (r = -0.217, p = 0.03). Multivariate regression analysis showed that change in the EPA+DHA/AA ratio was a significant predictor of percentage change in plaque volume and fibrous component volume (β = -0.221, p = 0.02, and β = -0.200, p = 0.04, respectively). In conclusion, decreases in serum n-3 to n-6 polyunsaturated fatty acid ratios are associated with progression in coronary atherosclerosis evaluated using virtual histology intravascular ultrasound in statin-treated patients with coronary artery disease.

Comparison of Arterial Remodeling and Changes in Plaque Composition Between Patients With Progression Versus Regression of Coronary Atherosclerosis During Statin Therapy (from the TRUTH Study)

Statin therapy produces regression of coronary artery plaques and reduces the incidence of coronary artery disease. However, not all patients show regression of coronary atherosclerosis after statin therapy. The purpose of the present study was to identify differences in clinical characteristics, serum lipid profiles, arterial remodeling, and plaque composition between patients with progression and those with regression of coronary atherosclerosis during statin therapy. The effects of 8-month statin therapy on coronary atherosclerosis were evaluated in the Treatment With Statin on Atheroma Regression Evaluated by Intravascular Ultrasound With Virtual Histology (TRUTH) study using intravascular ultrasound-virtual histology. One hundred nineteen patients were divided into 2 groups according to atheroma volume increase (progressors) or decrease (regressors) during an 8-month follow-up period. Fifty-one patients (43%) were categorized as progressors and the remaining 68 (57%) as regressors. External elastic membrane volume increased, although not significantly (0.8%, p = 0.34), and luminal volume decreased significantly (-5.3%, p = 0.0003) in progressors, while external elastic membrane volume decreased significantly (-3.2%, p <0.0001) and luminal volume increased (2.2%, p = 0.13) in regressors. The fibrous component increased significantly in progressors, while this component decreased in regressors. A strong positive correlation was observed between change in atheroma volume and change in fibrous volume (r = 0.812, p <0.0001). In conclusion, coronary arteries showed negative remodeling during statin-induced plaque regression. The difference in plaque composition between patients with progression and those with regression of coronary atherosclerosis during statin therapy arose from the difference in the change in fibrous component.

Comparison of Change in Coronary Atherosclerosis in Patients With Stable Versus Unstable Angina Pectoris Receiving Statin Therapy (from the Treatment With Statin on Atheroma Regression Evaluated by Intravascular Ultrasound With Virtual Histology [TRUTH] Study)

Although statin-induced regression in coronary atherosclerosis seems to be greater in patients with acute coronary syndrome than in those with stable coronary artery disease, no reports have examined this. The purpose of the present study was to compare the changes in coronary atherosclerosis in patients with stable versus unstable angina pectoris (AP). The effects of 8-month statin therapy on coronary atherosclerosis were evaluated using virtual histology intravascular ultrasound, and analyzable intravascular ultrasound data were obtained from 119 patients (83 patients with stable AP and 36 with unstable AP). A significant decrease in plaque volume was observed in patients with unstable AP (-2.2%, p = 0.02) but not in patients with stable AP. A significant increase in the necrotic-core component (0.30 mm(3)/mm, p = 0.009) was observed only in patients with unstable AP. Significant positive correlations were observed between the percentage of change in platelet-activating factor acetylhydrolase and the percentage of change in plaque volume (r = 0.346, p = 0.05) in patients with unstable AP. No significant correlations were observed in patients with stable AP. Multivariate regression analyses showed that a reduction in platelet-activating factor acetylhydrolase was associated with regression in coronary atherosclerosis, particularly of the fibrous component (β = 0.443, p = 0.003), in patients with unstable AP. In conclusion, regression of the coronary artery plaque volume was greater, although statin therapy did not halt the increases in plaque vulnerability, in patients with unstable AP compared to those with stable AP. A reduction in the serum platelet-activating factor acetylhydrolase level was associated with regression in coronary atherosclerosis, particularly the fibrous plaque volume, in patients with unstable AP.

Long-term prognosis of patients with acute myocardial infarction in the era of acute revascularization (from the Heart Institute of Japan Acute Myocardial Infarction [HIJAMI] registry)☆

BACKGROUND The long-term prognosis of patients with acute myocardial infarction (AMI) in the contemporary acute revascularization era is not fully understood. METHODS To clarify long-term prognosis and prognostic factors of AMI patients in a real-world setting, we consecutively registered 3021 patients with AMI (mean age 69 years, 70.7% male) who were admitted to 17 participating medical institutions and followed up prospectively. The outcome measure was death from any cause. RESULTS Among 3021 patients, 629 patients had non-ST elevation MI (non-STEMI). During the index hospitalization, coronary angioplasty and thrombolytic therapy were performed in 58.1% and 16.3% of patients, respectively. During hospitalization, 285 patients (9.4%) died. Among 2736 patients (90.6%) who were discharged alive and followed for a median of 4.3 years (follow-up rate, 97.1%), 434 patients (15.9%) died. Among them, 250 (57.6%) died from non-cardiac causes. Compared with STEMI patients, non-STEMI patients suffered significantly more adverse outcomes. Advanced age and non-STEMI disease were associated with poorer outcomes. Multivariate analysis revealed that diabetes mellitus, acute-phase heart failure (Killip functional class ≥ 2), higher serum creatinine level (≥ 1.2 mg/dl), and advanced age (≥ 70 years and ≥ 80 years) at the onset of the AMI were independent poor prognostic factors (hazard ratios, 1.07, 2.53, 1.89, 2.50, and 6.80 respectively). CONCLUSIONS AMI patients in the era of acute revascularization have favorable long-term prognoses, and a large proportion of late deaths are non-cardiac in nature. The establishment of an optimal management strategy for elderly AMI patients, AMI patients with diabetes, and non-ST elevation AMI patients are essential.

Low serum docosahexaenoic acid is associated with progression of coronary atherosclerosis in statin-treated patients with diabetes mellitus: results of the treatment with statin on atheroma regression evaluated by intravascular ultrasound with virtual histology (TRUTH) study

BackgroundDiabetes mellitus (DM) accelerates plaque progression despite the use of statin therapy. The purpose of the present study was to evaluate the determinants of atheroma progression in statin-treated patients with DM.MethodsCoronary atherosclerosis in nonculprit lesions in a vessel undergoing percutaneous coronary intervention (PCI) was evaluated using virtual histology intravascular ultrasound. The study included 50 patients with DM who had been taking statin therapy for 8 months at the time of PCI.ResultsTwenty-six patients (52%) showed atheroma progression (progressors) and the remaining 24 patients (48%) showed atheroma regression (regressors) after 8 months of follow-up. Fewer progressors than regressors received intensive lipid-lowering therapy with pitavastatin (31% vs. 50%, p = 0.17) and the frequency of insulin use was higher in progressors (31% vs. 13%, p = 0.18). However, neither of these differences reached statistical significance. Risk factor control at baseline and at the 8-month follow-up did not differ between the 2 groups except for serum levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Univariate regression analysis showed that serum EPA (r = -0.317, p = 0.03) and DHA (r = -0.353, p = 0.02) negatively correlated with atheroma progression. Multivariate stepwise regression analysis showed that low serum DHA and pravastatin use were significant independent predictors for atheroma progression during statin therapy (DHA: β = -0.414, type of statin: β = -0.287, p = 0.001).ConclusionsLow serum DHA is associated with progression of coronary atherosclerosis in statin-treated patients with DM.Trial registrationUMIN Clinical Trials Registry, UMIN ID: C000000311.

Long-term nitrate use in acute myocardial infarction (the Heart Institute of Japan, Department of Cardiology nitrate evaluation program).

BackgroundThe lack of any randomized controlled trials demonstrating a beneficial effect of nitrates for the secondary prevention of coronary artery disease leads to a negative recommendation in current practice guidelines. The aim of the present study was to examine the efficacy of nitrate therapy for the treatment of acute myocardial infarction (AMI) in the contemporary revascularization era.Methods and resultsOf 2,736 consecutive patients with AMI (1,677 on nitrate therapy and 1,059 control patients not receiving nitrates), 1,766 patients were matched according to a propensity score (883 receiving nitrates and 883 control subjects). Before propensity score matching, the patients treated with nitrates were significantly older, had a higher Killip class, and underwent less aggressive revascularization and less modern pharmacotherapy compared with the patients who were not given nitrates. A total of 117 patients (11.0%) died in the control group and 317 patients (18.9%) in the nitrate group (hazard ratio, 1.70; 95% CI, 1.38–2.10; P < 0.001) during a 5-year follow-up period. In contrast, among propensity score-matched patients, 110 patients (12.5%) died in the control group and 126 patients died (14.3%) in the nitrate group (hazard ratio, 1.06; 95% CI 0.82–1.36, P = 0.678). The 1-, 3- and 5-year cumulative mortality rates (Kaplan–Meier method) were respectively 4.5%, 9.8%, and 14.1% in the control group versus 5.2%, 9.8%, and 14.8% in the nitrate group. There were also no statistical or clinical differences between the two matched groups with regard to the other endpoints assessed.ConclusionsOur results suggest that nitrate therapy does not increase mortality and cardiac events in AMI patients. Our results differ from those of previous observational studies, suggesting that new prospective randomized clinical trials are needed in the current revascularization era.

Comparison of the effects of pitavastatin versus pravastatin on coronary artery plaque phenotype assessed by tissue characterization using serial virtual histology intravascular ultrasound

Thin-cap fibroatheroma (TCFA) is the most common type of vulnerable plaque and is the precursor of plaque rupture. However, rupture of a TCFA is not the only mechanism underlying thrombus formation or acute coronary syndrome. Although statin therapy changes the composition of coronary artery plaques, the effects of statins, particularly different types of statins, on plaque phenotype have not been fully examined. This study compared the effects of pitavastatin versus pravastatin on coronary artery plaque phenotype assessed by virtual histology (VH) intravascular ultrasound (IVUS) in patients with angina pectoris (AP). Coronary atherosclerosis in nonculprit lesions was evaluated using VH-IVUS at baseline and 8 months after statin therapy; analyzable IVUS data were obtained from 83 patients with stable AP (39 patients treated with pitavastatin and 44 with pravastatin) and 36 patients with unstable AP (19 patients treated with pitavastatin and 17 with pravastatin). Pitavastatin had a strong effect on reducing pathologic intimal thickening (PIT), especially in patients with unstable AP, but had no impact on VH-TCFA or fibroatheroma (FA). By contrast, pravastatin had weak effects on reducing PIT, VH-TCFA, or FA. Increases in the number of calcified plaques were observed for both statins. In conclusion, pitavastatin and pravastatin changed coronary artery plaque phenotype as assessed by VH-IVUS in patients with AP. However, the effects of these statins on coronary artery plaque phenotype were different.

Effects of Statins on Serum n-3 to n-6 Polyunsaturated Fatty Acid Ratios in Patients With Coronary Artery Disease

Background: A low n-3 to n-6 polyunsaturated fatty acids (PUFAs) ratio is reported to be associated with cardiovascular events. However, the effects of statins on this ratio have not been fully examined. Methods: A total of 101 patients with coronary artery disease, who were not receiving lipid-lowering therapy were randomly assigned to receive either 4 mg/day of pitavastatin or 20 mg/day of pravastatin. Serum PUFA levels were measured at baseline and 8 months after treatment with statins. Results: Pitavastatin was used to treat 51 patients and the remaining 50 patients were treated using pravastatin. A significant positive correlation was observed between the percent change in low-density lipoprotein cholesterol and that in dihomogamma-linolenic acid (r = .376, P = .007), arachidonic acid (AA; r = .316, P = .02), eicosapentaenoic acid (EPA; r = .408, P = .003), or docosahexaenoic acid (DHA; r = .270, P = .056) in the pitavastatin group. However, these correlations were not observed in the pravastatin group. The DHA/AA ratio decreased significantly in the pitavastatin group only (from 0.96 to 0.83, P = .0002) and the DHA/AA ratio was significantly lower in the pitavastatin group at 8 months (0.83 vs 0.96, P = .03). The EPA/AA ratio did not show significant changes in either group. Conclusions: Pitavastatin decreased the serum DHA/AA ratio, whereas pravastatin had no effect on this ratio. Neither pitavastatin nor pravastatin had an effect on the serum EPA/AA ratio in patients with coronary artery disease.