Efficacy of Statin Therapy in Inducing Coronary Plaque Regression in Patients with Low Baseline Cholesterol Levels.

AIM: The efficacy of statin therapy in inducing coronary plaque regression may depend on baseline cholesterol levels. We aimed to determine the efficacy of statin therapy in inducing coronary plaque regression in statin-naïve patients with low cholesterol levels using serial intravascular ultrasound (IVUS) data from the treatment with statin on atheroma regression evaluated by virtual histology IVUS (TRUTH) study. METHODS: The TRUTH study is a prospective, multicenter trial, comparing the efficacies of pitavastatin and pravastatin in coronary plaque regression in 164 patients. All patients were statin-naïve and received statin therapy only after study enrollment. The primary endpoint was the observation of coronary plaque progression, despite statin therapy. RESULTS: Serial IVUS data, at baseline and after an 8-month follow-up, were available for 119 patients. The patients were divided into three groups based on non-high-density lipoprotein cholesterol (HDL-C) levels-low: ≤140 mg/dl, n=38; moderate: 141-169 mg/dl, n=42; and high: ≥170 mg/dl, n=39. Coronary plaque progression was noted in the low cholesterol group, whereas plaque regression was noted in the moderate and high cholesterol groups [%Δplaque volume: 2.3±7.4 vs. －2.7± 10.7 vs. －3.2±7.5, p=0.004 (analysis of variance)]. After adjusting for all variables, a low non-HDL-C level (≤140 mg/dl) was identified as an independent predictor of coronary plaque progression [odds ratio, 3.7; 95% confidence interval, 1.5-9.1, p=0.004]. CONCLUSION: Serial IVUS data analysis indicated that statin therapy was less effective in inducing coronary plaque regression in patients with low cholesterol levels but more effective in those with high cholesterol levels at baseline.University Hospital Medical Information Network (UMIN) (UMIN ID: C000000311).

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.

Lipoprotein(a) is associated with necrotic core progression of non-culprit coronary lesions in statin-treated patients with angina pectoris.

BACKGROUND: Statin therapy results in regression and stabilization of coronary artery plaques, and reduces the incidence of coronary artery disease. However, statin therapy does not effectively halt the accumulation of necrotic core in all patients. The purpose of the present study was to identify the predictors associated with necrotic core progression during statin therapy. METHODS: Coronary atherosclerosis in non-culprit lesions was evaluated using virtual histology intravascular ultrasound at baseline and 8 months after statin therapy. One hundred nineteen patients were divided into 2 groups based on necrotic core progression or regression during an 8-month follow-up period. RESULTS: Patients with necrotic core progression had higher serum lipoprotein(a) [Lp(a)] levels than patients with regression at baseline (16 mg/dL vs. 12 mg/dL, p = 0.02) and at the 8-month follow-up (17 mg/dL vs. 10 mg/dL, p = 0.006). Patients with necrotic core progression had a higher fibro-fatty plaque volume (1.28 mm³/mm vs. 0.73 mm³/mm, p = 0.002), and less necrotic core (0.56 mm³/mm vs. 1.04 mm³/mm, p < 0.0001) and dense calcium (0.35 mm³/mm vs. 0.56 mm³/mm, p = 0.006) plaque volumes at baseline than patients with regression. Multivariate logistic regression analysis showed that Lp(a) was a significant independent predictor associated with necrotic core progression during statin therapy (odds ratio [OR]: 3.514; 95% confidence interval [CI]: 1.338-9.228; p = 0.01). CONCLUSIONS: Serum Lp(a) is independently associated with necrotic core progression in statin-treated patients with angina pectoris.

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.

BACKGROUND: Diabetes 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. METHODS: Coronary 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. RESULTS: Twenty-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: ß = -0.414, type of statin: ß = -0.287, p = 0.001). CONCLUSIONS: Low serum DHA is associated with progression of coronary atherosclerosis in statin-treated patients with DM. TRIAL REGISTRATION: UMIN Clinical Trials Registry, UMIN ID: C000000311.

Impacts of age on coronary atherosclerosis and vascular response to statin therapy.

Age is a well-established risk factor for cardiovascular disease. Recent trials using intravascular ultrasound (IVUS) have shown that lipid-lowering therapy with statins halts the progression or induces the regression of coronary artery plaques. However, impacts of age on coronary atherosclerosis and vascular response to statin therapy have not been fully evaluated. The effects of 8-month statin therapy on coronary atherosclerosis were evaluated using virtual histology-IVUS. IVUS data were analyzed from 119 patients who were divided into two groups according to age: elderly patients (≥65 years, n = 72) and non-elderly patients (<65 years, n = 47). No patients were taking statins or other lipid-lowering therapies at baseline. At baseline, external elastic membrane (EEM) volume (17.27 vs. 14.95 mm(3)/mm, p = 0.02) and plaque volume (9.49 vs. 8.11 mm(3)/mm, p = 0.03) in the elderly patients were significantly greater than in the non-elderly patients. The EEM volume (-2.4 %, p = 0.007) and plaque volume (-3.1 %, p = 0.007) after 8-month of statin therapy had significantly decreased in the non-elderly patients but not in the elderly patients. A significant positive correlation was observed between age and percentage change in plaque volume (r = 0.265, p = 0.004). A multivariate regression analysis showed that age was a significant predictor of the percentage change in plaque volume during statin therapy (ß = 0.223, p = 0.02). Coronary atherosclerosis was more advanced and vascular responses to statin therapy were attenuated in the elderly patients compared to the non-elderly patients.

Comparison of effects of serum n-3 to n-6 polyunsaturated fatty acid ratios on coronary atherosclerosis in patients treated with pitavastatin or pravastatin undergoing percutaneous coronary intervention.

A low n-3 to n-6 polyunsaturated fatty acid (PUFA) ratio is associated with cardiovascular events. However, the effects of this ratio on coronary atherosclerosis have not been fully examined, particularly in patients treated with different types of statins. This study compared the effects of n-3 to n-6 PUFA ratios on coronary atherosclerosis in patients treated with pitavastatin and pravastatin. 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. Pitavastatin and pravastatin were used to treat 51 and 50 patients, respectively. Changes in the docosahexaenoic acid (DHA)/arachidonic acid (AA) and eicosapentaenoic acid+DHA/AA ratios were not correlated with the percentage change in plaque volume in the pitavastatin group, whereas the percentage change in plaque volume and the changes in the DHA/AA ratio (r = -0.404, p = 0.004) and eicosapentaenoic acid+DHA/AA ratio (r = -0.350, p = 0.01) in the pravastatin group showed significant negative correlations. Multivariate regression analysis showed that age (ß = 0.306, p = 0.02), the presence of diabetes mellitus (ß = 0.250, p = 0.048), and changes in the DHA/AA ratio (ß = -0.423, p = 0.001) were significant predictors of the percentage change in plaque volume in patients treated with pravastatin. In conclusion, decreases in n-3 to n-6 PUFA ratios are associated with progression in coronary atherosclerosis during pravastatin therapy but not during pitavastatin therapy.

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 (ß = 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.

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.

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 (ß = -0.221, p = 0.02, and ß = -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.

Impact of diabetes mellitus on coronary atherosclerosis and plaque composition under statin therapy ­ subanalysis of the TRUTH study ­.

BACKGROUND: Patients with diabetes mellitus (DM) have a markedly increased incidence of adverse cardiovascular events, but the mechanisms have not been well-characterized. METHODS AND RESULTS: The TRUTH study evaluated the effects of 8-month statin therapy on coronary artery plaque composition using virtual histology intravascular ultrasound (IVUS). Analyzable IVUS data were obtained from 119 patients, including 50 DM patients. The pattern of arterial remodeling, extent of coronary atherosclerosis, and plaque composition were compared in subjects with and without DM. Significant decreases in atheroma volume (-2.3%, P=0.02) and external elastic membrane volume (-1.7%, P=0.02) were observed only in the non-DM group. Although statin therapy significantly decreased the fibro-fatty component in both groups, this component at follow-up was significantly greater in the DM group (0.99 mm(3)/mm vs. 0.70 mm(3)/mm, P=0.03). Multivariate regression analysis showed that the presence of DM was associated with greater atheroma volume (ß=0.203, P=0.02), particularly fibro-fatty plaque volume at follow-up (ß=0.215, P=0.01). CONCLUSIONS: DM attenuated the degree of regression of coronary atherosclerosis under statin therapy. A large amount of fibro-fatty plaque volume under statin therapy may affect the development of coronary events in patients with DM.

Impacts of conventional coronary risk factors, diabetes and hypertension, on coronary atherosclerosis during statin therapy: subanalysis of the TRUTH study.

OBJECTIVE: Patients with diabetes mellitus (DM) and hypertension (HT) are at a high risk of coronary artery disease. However, the mechanisms underlying this have not been well characterized. The purpose of the present study was to evaluate the impacts of DM and HT on coronary atherosclerosis during statin therapy. MATERIALS AND METHODS: The effects of 8-month statin therapy on coronary atherosclerosis were evaluated in the TRUTH study using virtual histology intravascular ultrasound. Analyzable intravascular ultrasound data were obtained from 119 patients who were divided into four subgroups, namely, group A: DM (+), HT (+); group B: DM (+), HT (-); group C: DM (-), HT (+); and group D: DM (-), HT (-). The pattern of arterial remodeling, extent of coronary atherosclerosis, and plaque composition were compared among the four subgroups. RESULTS: Atheroma volume decreased significantly in group D (-3.9%, P=0.01), whereas it tended to increase in group A (1.0%, P=0.77). A significant difference in the mean percent change of atheroma volume was observed between groups A and D (1.0 vs. -3.9%, P=0.03). Furthermore, the frequency of progression in atheroma volume was significantly higher in group A (60, 33, 45, and 24% in groups A, B, C, and D, respectively; P=0.03). No significant differences in the changes in the four plaque components among the four subgroups were observed. CONCLUSION: A combination of DM and HT attenuates the degree of regression of coronary atherosclerosis, but does not influence changes in plaque composition during statin therapy.

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.

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.

Treatment with statin on atheroma regression evaluated by intravascular ultrasound with Virtual Histology (TRUTH Study): rationale and design.

BACKGROUND: Many clinical trials have shown that 3-hydroxy-3-methylglutaryl-conenzyme A reductase inhibitors (statins) can significantly reduce the incidence of coronary artery disease in both primary and secondary prevention. A recent study showed that aggressive lipid-lowering therapy with statins could achieve regression of coronary artery plaque evaluated with gray-scale intravascular ultrasound (IVUS). However, the actual changes in coronary artery plaque composition produced by statin therapy have not been well delineated. METHODS AND RESULTS: This study will be a prospective, open-label, randomized multicenter study of 160 patients with stable or unstable angina who have undergone percutaneous coronary intervention with Virtual Histology IVUS (VH-IVUS). Patients will be randomly assigned to either the pitavastatin or pravastatin group. After treatment for 24-40 weeks, VH-IVUS will be performed again in the same segment of the coronary artery. The primary endpoint will be quantitative changes in each of the 4 components measured by VH-IVUS. CONCLUSION: The treatment with statin on atheroma regression evaluated by intravascular ultrasound with Virtual Histology (TRUTH) study will be the first multicenter study using VH-IVUS to evaluate the effects of statins on changes in coronary artery plaque composition and the findings will clarify the mechanisms of coronary artery plaque stabilization.

Bone tissue engineering using human adipose-derived stem cells and honeycomb collagen scaffold.

Human adipose-derived stem cells (ASCs) have the capacity to regenerate and the potential to differentiate into multiple lineages of mesenchymal cells. The aim of this study was to investigate the possibility of using honeycomb collagen scaffold to culture ASCs in bone tissue engineering. The osteogenic capacity of ASCs in vitro, was confirmed by histology and measuring the expression of cbfa-1. After that, ASCs were cultured for up to 14 days in the honeycomb scaffold to allow a high density, three-dimensional culture. Scanning electron microscopy data showed that the scaffold was filled with the grown ASCs, and calcification, stained black with von Kossa, was confirmed. Furthermore, The ASC-loaded honeycomb collagen scaffolds cultured for 14 days were subcutaneously transplanted into nude mice, and excised after 8 weeks. Bone formation in vivo was examined using HE stain, von Kossa stain, and osteocalcin immunostain. Those histological views showed significant positive stains in the samples of osteogenic medium in the three types of stain. These results suggest that this carrier is a suitable scaffold for ASCs and will be useful as a three-dimensional bone tissue engineering scaffold in vitro and in vivo.

Analysis of osteochondro-induction using growth and differentiation factor-5 in rat muscle.

Growth and differentiation factor-5 (GDF-5) belongs to the TGF-beta super family, and reportedly plays an important role in cartilage development and differentiation. In this study, we implanted GDF-5 in rat leg muscle, and evaluated its in vivo osteochondro-inducing activity by histological and X-ray examinations. GDF-5 (0, 100, 300, and 500 microg) and the carrier type I collagen were mixed, and the mixture was implanted into rat leg muscle. Three weeks later, the site of implantation was examined by soft X-ray, and examined histologically. The GDF-5 0 and 100 microg groups showed no osteochondro-induction. The GDF-5 300 microg group showed aggregates of cartilage and some bone tissue in the carrier. The GDF-5 500 microg group revealed bone and no cartilage. This is the first report of the dose-dependent effect of GDF-5 inducing osteochondrogenesis or osteogenesis.