Moderate Lipid-lowering Therapy Research Articles

Metabonomic Biomarkers of Plaque Burden and Instability in Patients With Coronary Atherosclerotic Disease After Moderate Lipid-Lowering Therapy.

Contemporary risk assessment in patients with coronary atherosclerotic disease (CAD) often relies on invasive angiography. However, we aimed to explore the potential of metabolomic biomarkers in reflecting residual risk in patients with CAD after moderate lipid-lowering therapy. We analyzed serum metabolomic profile among 2560 patients with newly diagnosed CAD undergoing moderate lipid-lowering therapy, through nuclear magnetic resonance spectroscopy and quantified 175 metabolites, predominantly lipoproteins and their components. CAD severity was evaluated using Gensini score for plaque burden and circulating cardiac troponin T levels for plaque instability. The association of metabolites with CAD severity was examined using multivariate linear regression, and the underlying potential causality was explored using a 2-sample Mendelian randomization approach. Two composite metabolomic indices were constructed to reflect CAD severity using least absolute shrinkage and selection operator linear regression, and their associations with risk of major adverse cardiac events during a median follow-up of 3.8 years were evaluated using Cox models. Our investigation revealed that triglycerides and apolipoprotein B in low-density lipoprotein particles displayed stronger associations with CAD severity compared with the clinically used low-density lipoprotein cholesterol marker. In large high-density lipoprotein, components like cholesterol, cholesterol esters, triglyceride, apolipoprotein A1/A2 showed inverse associations with CAD severity. Certain metabolites, including apolipoprotein B and dihydrothymine, showed a putative causal link with Gensini score. Notably, per standard deviation increase in Gensini score-based metabolomic index was associated with 14.8% higher major adverse cardiac event risk (hazard ratio, 1.148 [95% CI, 1.018-1.295]) independent of demographic factors, medication use, and disease status. Our findings highlight the potential of nuclear magnetic resonance-based metabolomics in identifying novel biomarkers of plaque burden and instability. Metabolites related to plaque burden may facilitate noninvasive assessment of CAD prognosis.

Plasma ANGPTL8 Levels and Risk for Secondary Cardiovascular Events in Japanese Patients With Stable Coronary Artery Disease Receiving Statin Therapy.

The ability to predict secondary cardiovascular events could improve health of patients undergoing statin treatment. Circulating ANGPTL8 (angiopoietin-like protein 8) levels, which positively correlate with proatherosclerotic lipid profiles, activate the pivotal proatherosclerotic factor ANGPTL3. Here, we assessed potential association between circulating ANGPTL8 levels and risk of secondary cardiovascular events in statin-treated patients. We conducted a biomarker study with a case-cohort design, using samples from a 2018 randomized control trial known as randomized evaluation of high-dose (4 mg/day) or low-dose (1 mg/day) lipid-lowering therapy with pitavastatin in coronary artery disease (REAL-CAD [Randomized Evaluation of Aggressive or Moderate Lipid-Lowering Therapy With Pitavastatin in Coronary Artery Disease])." From that study's full analysis set (n=12 413), we selected 2250 patients with stable coronary artery disease (582 with the primary outcome, 1745 randomly chosen, and 77 overlapping subjects). A composite end point including cardiovascular-related death, nonfatal myocardial infarction, nonfatal ischemic stroke, or unstable angina requiring emergent admission was set as a primary end point. Circulating ANGPTL8 levels were measured at baseline and 6 months after randomization. Over a 6-month period, ANGPTL8 level changes significantly decreased in the high-dose pitavastatin group, which showed 19% risk reduction of secondary cardiovascular events compared with the low-dose group in the REAL-CAD [Randomized Evaluation of Aggressive or Moderate Lipid-Lowering Therapy With Pitavastatin in Coronary Artery Disease] study. In the highest quartiles, relative increases in ANGPTL8 levels were significantly associated with increased risk for secondary cardiovascular events, after adjustment for several cardiovascular disease risk factors and pitavastatin treatment (hazard ratio in Q4, 1.67 [95% CI, 1.17-2.39). Subgroup analyses showed relatively strong relationships between relative ANGPTL8 increases and secondary cardiovascular events in the high-dose pitavastatin group (hazard ratio in Q4, 2.07 [95% CI, 1.21-3.55]) and in the low ANGPTL8 group at baseline (166 <pmol/L, hazard ratio in Q4: 1.74, [95% CI, 1.04-2.93]). Monitoring ANGPTL8 levels over time might be useful to assess residual risk of cardiovascular secondary events in patients with cardiovascular disease undergoing statin therapy.

Thrombotic Risk Stratification and Intensive Statin Therapy for Secondary Prevention of Coronary Artery Disease - Insights From the REAL-CAD Study.

It is unknown whether beneficial effects of higher-dose statins on cardiovascular events are different according to the thrombotic risk in patients with chronic coronary syndrome (CCS). The Randomized Evaluation of Aggressive or Moderate Lipid-Lowering Therapy with Pitavastatin in Coronary Artery Disease (REAL-CAD) study is a randomized trial comparing 4 mg and 1 mg pitavastatin in patients with CCS. This study categorized 12,413 patients into 3 strata according to the CREDO-Kyoto thrombotic risk score: low-risk (N=9,434; 4 mg: N=4,742, and 1 mg: N=4,692), intermediate-risk (N=2,415; 4 mg: N=1,188, and 1 mg: N=1,227); and high-risk (N=564; 4 mg: N=269, and 1 mg: N=295). The primary endpoint was a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal ischemic stroke, or unstable angina. Cumulative 4-year incidence of the primary endpoint was significantly higher in the high-risk stratum than in the intermediate- and low-risk strata (11.0%, 6.3%, and 4.5%, P<0.0001). In the low-risk stratum, the cumulative 4-year incidence of the primary endpoint was significantly lower in the 4 mg than in the 1 mg group (4.0% and 4.9%, P=0.02), whereas in the intermediate- and high-risk strata, it was numerically lower in the 4 mg than in the 1 mg group. There was no significant treatment-by-subgroup interaction for the primary endpoint (P-interaction=0.77). High-dose pitavastatin therapy compared with low-dose pitavastatin therapy was associated with a trend toward lowering the risk for cardiovascular events irrespective of the thrombotic risk in patients with CCS.

Small Dense Low-Density Lipoprotein Cholesterol and Cardiovascular Risk in Statin-Treated Patients with Coronary Artery Disease.

Aim: We investigated the relationship between small dense low-density cholesterol (sdLDL-C) and risk of major adverse cardiovascular events (MACE) in patients treated with high- or low-dose statin therapy. Methods: This was a prospective case-cohort study within the Randomized Evaluation of Aggressive or Moderate Lipid-Lowering Therapy with Pitavastatin in Coronary Artery Disease (REAL-CAD) study, a randomized trial of high- or low-dose (4 or 1 mg/d pitavastatin, respectively) statin therapy, in patients with stable coronary artery disease (CAD). Serum sdLDL-C was determined using an automated homogenous assay at baseline (randomization after a rule-in period, ＞1 month with 1 mg/d pitavastatin) and 6 months after randomization, in 497 MACE cases, and 1543 participants randomly selected from the REAL-CAD study population. Results: High-dose pitavastatin reduced sdLDL-C by 20% than low-dose pitavastatin (p for interaction ＜0.001). Among patients receiving low-dose pitavastatin, baseline sdLDL-C demonstrated higher MACE risk independent of LDL-C (hazard ratio [95% confidence interval], 4th versus 1st quartile, 1.67 [1.04–2.68];p for trend=0.034). High-dose (versus low-dose) pitavastatin reduced MACE risk by 46% in patients in the highest baseline sdLDL-C quartile (＞34.3 mg/dL; 0.54 [0.36–0.81];p=0.003), but increased relative risk by 40% in patients with 1st quartile (≤ 19.5 mg/dL; 1.40 [0.94–2.09];p=0.099) and did not alter risk in those in 2nd and 3rd quartiles (p for interaction=0.002). Conclusions: These findings associate sdLDL-C and cardiovascular risk, independent of LDL-C, in statin-treated CAD patients. Notably, high-dose statin therapy reduces this risk in those with the highest baseline sdLDL-C.

Abstract 13337: Increased Serum Immunoglobulin G4 Level is a Novel Predictor of Cardiovascular Events Independent of Established Risk Factors: Results From the Real-cad Study

Background: Inflammation is a mediator of atherosclerosis progression. However, it remains unclear whether immunoglobulin G4 (IgG4)-related immuno-inflammation may play a specific role in cardiovascular disease. Methods: We used a case-cohort design to analyze the association of serum IgG4 levels with future cardiovascular events. The sample included 561 cases of the primary end point, defined as cardiovascular death, myocardial infarction, ischemic stroke, or unstable angina, and a random subcohort of 1688 (1409 males; mean age, 68.1 ± 8.4 years), of whom 73 were also cases, selected from 12413 eligible participants with stable coronary artery disease in the Randomized Evaluation of Aggressive or Moderate Lipid Lowering Therapy with Pitavastatin in Coronary Artery Disease (REAL-CAD) study. Results: This case-cohort study had a median follow-up of 3.9 years (interquartile range [IR] 2.9-4.6). Serum IgG4 levels at baseline were 45.3 mg/dL (IR 37.9-58.9), and 845 (50%) took high-dose statins in the subcohort sample. In Cox regression using age, gender, statin dose, high-sensitivity C-reactive protein (hsCRP), body mass index, estimated glomerular filtration rate (eGFR), hypertension, diabetes, and serum lipid profiles, including low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides, as covariates, the highest IgG4 quartile was predictive of the primary end point at 4 years (hazard ratio [HR] 1.44, 95% confidence interval [CI] 1.03-2.00, P=0.031), compared with the lowest quartile. Similar results were observed for the secondary end point, a composite of the primary end point plus coronary revascularization (HR 1.60, 95% CI 1.16-2.20, P=0.004). Conclusions: Elevated serum IgG4 level at baseline predicted long-term cardiovascular outcomes independent of established risk factors and high-dose statin therapy in patients with stable CAD. Serum IgG4 may reflect residual cardiovascular risk.

Impact of chronic kidney disease on mid-term prognosis of stable angina patients with high-dose or low-dose pitavastatin treatment: REAL-CAD sub-study

Abstract Background We previously demonstrated that high-dose (4 mg/day) compared with low-dose (1 mg/day) pitavastatin therapy significantly reduced cardiovascular events in Japanese patients with stable coronary artery disease in the Randomized Evaluation of Aggressive or Moderate Lipid Lowering Therapy with Pitavastatin in Coronary Artery Disease (REAL-CAD) study. However, little is known about whether the advantage of high-dose statins over low-dose statins is consistent among non-, mild, and moderate to severe chronic kidney disease (CKD) patients. Purpose The aim of this study was to clarify the effect of high-dose statins on cardiovascular events in Japanese patients with or without CKD. Methods The REAL-CAD study is a prospective, multicenter, randomized, open-label, blinded endpoint, physician-initiated superiority trial. In this sub-analysis of REAL-CAD study, patients were categorized into three groups according to estimated glomerular filtration rate (eGFR). Patients on hemodialysis were excluded in this study. The primary endpoint was a composite of cardiovascular death, non-fatal myocardial infarction (MI), non-fatal ischemic stroke, or unstable angina requiring emergency hospitalization. A secondary composite endpoint was defined as a composite of the primary endpoint event or clinically-indicated coronary revascularization excluding target-lesion revascularization. Results The total population of the REAL-CAD study was 12,413 patients. After exclusion of patients lacking eGFR data, the numbers of patients categorized into non-CKD (eGFR ≥60 mL/min/1.73m2), mild CKD (eGFR; 45–60), and moderate to severe CKD (eGFR &amp;lt;45) were 7,778 (64%), 3,176 (26%), and 1,164 (10%), respectively. The median follow-up period was 3.9 years. The baseline characteristics and medications were well balanced between the two groups in each CKD group. While high-dose compared to low-dose pitavastatin significantly reduced the primary endpoint in non-CKD patients, the effect was not observed in mild CKD and moderate to severe CKD patients (Figure 1). High-dose compared with low-dose pitavastatin did not significantly reduce the secondary composite endpoint in both mild and moderate to severe CKD patients as well. High-dose pitavastatin significantly reduced the risks of MI and any coronary revascularization in non-CKD patients, however, the effects were diminished in mild CKD and moderate to severe CKD patients. There was no significant difference between high-dose and low-dose pitavastatin treatment in the risk of all-cause death, cardiovascular death, ischemic stroke, or unstable angina requiring emergency hospitalization in patients with or without CKD. Conclusion Although high-dose pitavastatin therapy significantly reduced cardiovascular events in non-CKD patients with stable angina compared to low-dose pitavastatin, such beneficial effects had diminished in Japanese patients with mild or moderate to severe CKD patients. Figure 1. Kaplan-Meier Curves for Endpoints Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Clinical Research of Lifestyle-Related Disease of the Public Health Research Foundation

High-density lipoprotein cholesterol does not predict future cardiovascular events in patients treated with statins for secondary prevention: an observation from the REAL-CAD study

Abstract Background The relation between high-density lipoprotein cholesterol (HDL-C) level after statin therapy and cardiovascular events in patients with stable coronary artery disease remains unclear. Purpose We sought to determine the association of the HDL-C level after statin therapy with cardiovascular events in stable coronary artery disease patients. Methods This study was a post-hoc analysis of the Randomized Evaluation of Aggressive or Moderate Lipid Lowering Therapy with Pitavastatin in Coronary Artery Disease (REAL-CAD) study, which is randomised, open-label, blinded endpoint, physician-initiated, superiority clinical trial. Enrollment was from January 2010 to March 2013, and follow-up was through January 2016. From the main study, we excluded the patients without either HDL-C data at baseline or 6 months, with occurrence of the primary outcome at 6 months and reported poor adherence for pitavastatin. The primary outcome of interest was a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal ischemic stroke, or unstable angina requiring emergent admission after 6 months from randomisation, consistent with the primary analysis of the trial. We constructed landmark Cox proportional hazards regression models with the 18 selected clinically relevant risk-adjusting variables during the entire follow-up period starting at 6 months after randomisation. Absolute and relative changes of HDL-C level were defined as (6 months value – baseline value) and (absolute change / baseline value) × 100, respectively. Results Among 14,774 participants in the REAL-CAD study, 9,221 patients were included in this analysis (7652 [83.0%] male; median [IQR] age, 70 [63–75] years; median [IQR] HDL-C, 49 [42–57] mg/dL; median [IQR] low-density lipoprotein cholesterol [LDL-C], 88 [75–101] mg/dL). During a median follow-up period of 4.0 (IQR 3.2–4.7) years, the primary outcome occurred in 417 (4.5%) patients. There was no significant difference in crude and adjusted cumulative incidence of the primary outcome among the quartiles of HDL-C level at 6 months (Figure 1). The adjusted risks of all the HDL-C related variables (baseline value, 6 months value, absolute and relative changes) for the primary outcome were not significant (Figure 2). Furthermore, the adjusted hazard ratio (HR) as HDL-C level at 6 months increased by 10 mg/dL remained non-significant for the primary outcome for each on-treatment LDL-C level at 6 months (&amp;lt;70 mg/dL [HR 0.97, 95% CI 0.82–1.15], 70–100 mg/dL [HR 1.10, 95% CI 0.98–1.24], and ≥100 mg/dL [HR 0.94, 95% CI 0.78–1.13]). There was also no significant association between HDL-C level at 6 months and the primary outcome both in the low (1 mg/day [HR 1.02, 95% CI 0.91–1.14], increased by 10 mg/dL) dose and high (4 mg/day [HR 1.04, 95% CI 0.91–1.19]) dose pitavastatin groups Conclusion After statin therapy with modestly controlled LDL-C, HDL-C level has little prognostic value in patients with stable coronary artery disease. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): The Comprehensive Support Project for Clinical Research of Lifestyle-Related Disease of the Public Health Research Foundation

Rationale and Design of Randomized Evaluation of Aggressive or Moderate Lipid Lowering Therapy with Pitavastatin in Coronary Artery Disease (REAL-CAD) Trial.

Large-scale clinical trials in patients in Western countries with coronary artery disease (CAD) have found that aggressive lipid-lowering therapy using high-dose statins reduces cardiovascular (CV) events further than low-dose statins. However, such evidence has not yet been fully established in Asian populations, including in Japan. The Randomized Evaluation of Aggressive or Moderate Lipid-Lowering Therapy with Pitavastatin in Coronary Artery Disease (REAL-CAD) study addresses whether intensification of statin therapy improves clinical outcomes in Japanese patients with CAD.REAL-CAD is a prospective, multicenter, randomized, open-label, blinded-endpoint, physician-initiated phase 4 trial in Japan. The study will recruit up to 12,600 patients with stable CAD. Patients are assigned to receive either pitavastatin 1 mg/day or pitavastatin 4 mg/day. LDL-C levels are expected to reach approximate mean values of 100 mg/dL in the low-dose pitavastatin group and 80 mg/dL in the high-dose group. The primary endpoint is the time to occurrence of a major CV event, including CV death, non-fatal myocardial infarction, non-fatal ischemic stroke, and unstable angina requiring emergency hospitalization during an average of 5 years. The large number of patients and the long follow-up period in the REAL-CAD study should ensure that there is adequate power to definitively determine if reducing LDL-C levels to approximately 80 mg/dL by high-dose statin can provide additional clinical benefit.After the study is completed, we will have categorical evidence on the optimal statin dose and target LDL-C level for secondary prevention in Japanese patients.

Expression of miR-23a induces telomere shortening and is associated with poor clinical outcomes in patients with coronary artery disease.

Telomeric repeat binding factor (TRF) 2 (TRF2) plays an important role in telomere maintenance. miR-23a may directly inhibit TRF2 expression, thereby, inducing telomere shortening and cellular senescence. The present study aimed to determine whether miR-23a and TRF2 are expressed in patients with coronary artery disease (CAD), and whether pitavastatin might affect these levels. The present study included 104 patients with CAD and 50 controls. Patients with CAD were randomly divided into two subgroups (a moderate lipid lowering therapy (LLT) group and an aggressive LLT group). Peripheral blood mononuclear cells (PBMCs) were taken from patients with CAD and from controls at baseline and after 12 months. Levels of miR-23a were higher in the CAD group than in the controls. Levels of TRF2 protein were lower in the CAD group than in the controls. Our randomized clinical study showed that aggressive LLT decreased miR-23a and increased TRF2 levels, whereas moderate LLT generated no change in these levels. Our transfected cell model showed that miR-23a controlled TRF2 expression. After a mean follow-up of 339 days, cardiovascular events were associated with high miR-23a, low TRF2 or low relative telomere length. Multivariate analysis showed that levels of miR-23a (RR: 4.9, 95% CI: 1.9-14.3) were a strong predictor of cardiovascular events after adjustment for baseline characteristics. In conclusion, elevated levels of miR-23a play an important role in coronary atherosclerosis via down-regulated TRF2, and may provide important prognostic information in patients with CAD. Additionally, aggressive LLT may prevent telomere erosion via down-regulated miR-23a.

Lower the Low-density Lipoprotein Cholesterol to the Level When You Born

Lower the Low-density Lipoprotein Cholesterol to the Level When You Born

Comparison of Intensive Versus Moderate Lipid-Lowering Therapy on Fibrous Cap and Atheroma Volume of Coronary Lipid-Rich Plaque Using Serial Optical Coherence Tomography and Intravascular Ultrasound Imaging

Despite marked clinical benefit, reduction in atheroma volume with statin therapy is minimal. Changes in plaque composition may explain this discrepancy. We aimed in the present study to assess the effect of statin therapy on coronary plaque composition and plaque volume using serial multimodality imaging. From an open-label, single-blinded study, patients with angiographically mild-to-moderate lesion were randomized to receive atorvastatin 60 (AT 60) mg or atorvastatin 20 (AT 20) mg for 12 months. Optical coherence tomography was used to assess fibrous cap thickness (FCT) and intravascular ultrasound to assess atheroma burden at 3 time points: baseline, at 6 months, and at 12 months. Thirty-six lipid-rich plaques in 27 patients with AT 60 mg and 30 lipid-rich plaques in 19 patients with AT 20 mg were enrolled in this study. Low-density lipoprotein cholesterol level was significantly decreased at 6 months without further reduction at 12 months. AT 60 mg induced greater reduction in low-density lipoprotein cholesterol compared with AT 20 mg. Optical coherence tomography revealed continuous increase in FCT from baseline to 6 months and to 12 months in both groups. AT 60 mg induced greater increase in FCT compared with AT 20 mg at both follow-up points. The prevalence of thin-cap fibroatheroma and the presence of macrophage at 6 months were significantly lower in AT 60 mg compared with AT 20 mg. Plaque burden did not change significantly in both groups. In conclusion, both intensive and moderate statin therapy stabilizes coronary plaques, with a greater benefit in the intensive statin group. However, no significant changes in plaque volume were observed over time regardless of the intensity of statin therapy.

Abstract 16064: Effect of Intensive versus Moderate Lipid-Lowering Therapy on the Progression of Coronary Lipid-Rich Plaque: A Prospective, Randomized, Serial Combined Optical Coherence Tomography and Intravascular Ultrasound Study

Background: Despite dramatic improvements in clinical outcome, intravascular ultrasound (IVUS) trials have shown minimal improvement of atheroma volume with statin therapy. Changes in plaque composition rather than plaque volume may contribute to the marked clinical benefit. Objectives: To assess the effect of intensive versus moderate lipid-lowering therapy on fibrous cap thickness (FCT) by optical coherence tomography (OCT) and percent atheroma volume (PAV) by IVUS. Methods: The patients with ≥1 non-treated lipid-rich plaque (LRP) with moderate stenosis were randomized to receive atorvastatin 60 mg (AT60), or atorvastatin 20 mg (AT20). OCT and IVUS imaging were performed at baseline, 6 months and 12 months. The primary endpoint was the change in FCT. The secondary endpoints were the change in PAV and the percent change in normalized total atheroma volume (%NTAV). Sixty-six LRP in 46 patients defined by OCT were studied. Results: Low-density lipoprotein cholesterol (LDL-C) was reduced significantly in both groups at 6 months; however, there was no further reduction at 12 months (Fig A, C). OCT demonstrated a continuous increase in FCT over time in both groups, with greater increase in the AT60 group than the AT20 group at 6 months (139.7±160.9% vs. 68.1±83.9%, p=0.021) and 12 months (211.3±125.4% vs. 120.2±136.9%, p&lt;0.0001) (Fig B, D). IVUS showed no significant changes in PAV and NTAV over time in two groups. The changes in PAV were similar between the two groups at 6 months (-0.48±3.4% in AT60 vs. 0.28±5.2% in AT20, p=0.50) and 12 months (-0.26±4.3% vs. 0.11±4.1%, p=0.73). %NTAV were also comparable between the two groups at 6 months and at 12 months. Conclusions: Intensive atorvastatin therapy induces more rapid and effective stabilization of coronary lipid-rich plaques by increasing FCT, as compared with moderate atorvastatin therapy. IVUS analysis did not show significant change in plaque volume over time in both groups.

Effect of Intensive Versus Moderate Lipid-Lowering Therapy on Epicardial Adipose Tissue in Hyperlipidemic Post-Menopausal Women: A Substudy of the BELLES Trial (Beyond Endorsed Lipid Lowering with EBT Scanning)

This study sought to evaluate the effect of intensive and moderate statin therapy on epicardial adipose tissue (EAT). EAT has been associated with coronary artery disease severity and outcome. It is currently unknown whether EAT volume changes over time when patients are exposed to statin therapy. Subanalysis of a randomized study of atorvastatin 80 mg/day versus pravastatin 40 mg/day for 1 year in a clinical trial designed to assess the progression of coronary artery calcium (CAC) in hyperlipidemic post-menopausal women. Patients underwent cardiac computed tomography scans at the start and end of the trial period. Of 420 patients, 194 received atorvastatin and 226 pravastatin; the median low-density lipoprotein change was -53.3% and -28.3% with atorvastatin and pravastatin, respectively (p < 0.001). Baseline EAT correlated with age, body mass index, hypertension, diabetes mellitus, high-density lipoprotein, triglyceride levels, and CAC (p < 0.001). At the end of follow-up, EAT regressed more in the atorvastatin than in the pravastatin group (median, -3.38% vs. -0.83%, p = 0.025). The EAT percent change from baseline was significant in the atorvastatin, but not the pravastatin group (p < 0.001 and p = 0.2, respectively). There was no correlation between lipid lowering and EAT regression. CAC progressed significantly in both groups from baseline. In hyperlipidemic post-menopausal women, statin therapy induced EAT regression, although intensive therapy was more effective than moderate-intensity therapy. This effect does not seem linked to low-density lipoprotein lowering and may be secondary to other actions of statins such as anti-inflammatory effects.

Comparison of Effects of Pitavastatin Versus Pravastatin on Serum Proprotein Convertase Subtilisin/Kexin Type 9 Levels in Statin-Naive Patients With Coronary Artery Disease

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key regulator of serum low-density lipoprotein cholesterol levels. Although statins increase serum PCSK9 levels, the effects of different types of statins on the serum PCSK9 levels have not been examined in detail. The purpose of the present study was to compare the effects of pitavastatin versus pravastatin on the serum PCSK9 levels. A total of 164 patients with coronary artery disease who were not receiving lipid-lowering therapy were randomly assigned to receive either 4mg/day of pitavastatin (intensive lipid-lowering therapy) or 20 mg/day of pravastatin (moderate lipid-lowering therapy). The serum PCSK9 levels were measured before statin treatment and 8 months after therapy. A significantly greater reduction in low-density lipoprotein cholesterol was observed in the pitavastatin group (-41% vs-28%, p= 0.0001). The serum levels of total PCSK9 and heterodimer PCSK9 significantly increased from 192 to 249 ng/ml (37%, p <0.0001) and 147 to 206 ng/ml (78%, p <0.0001) in the pitavastatin group and from 192 to 249 ng/ml (39%, p <0.0001) and 143 to 201 ng/ml (65%, p <0.0001) in the pravastatin group, respectively. The increase in total and heterodimer PSCK9 did not differ between the 2 groups. No significant correlations were found between the percentage of changes in heterodimer PCSK9 and changes in the various lipid parameters in either group. In conclusion, significant increases in the total and heterodimer PSCK9 levels were observed at 8 months after treatment with pitavastatin and pravastatin; however, these increases did not differ between the 2 statins.

Predictors of Statin-Induced Regression of Left Anterior Descending Coronary Artery Wall Thickness as Measured by High-Resolution Transthoracic Echocardiography

Statin therapy has been shown to reduce cardiovascular risk after myocardial infarction (MI). Using a novel technique of high-resolution transthoracic echocardiography (HRTTE), we sought to assess the statin-induced changes in left anterior descending coronary artery (LAD) wall thickness in previously statin naive patients over a 12-month period. Thirty subjects underwent HRTTE assessment of their LAD wall thickness predischarge post-MI (non-LAD territory) and at 3, 6, and 12 months. The LAD anterior and posterior wall thickness and vessel luminal diameter were measured. Blood lipid levels were also assessed at each study visit. All subjects were started on moderate lipid-lowering therapy (40 mg of atorvastatin or simvastatin). There was a sustained decrease in total cholesterol (-23%), triglycerides (-19%), and low-density lipoprotein (-41%) at the 3-month visit from the baseline, with no change in high-density lipoprotein level. Overall, there was no change in the LAD wall thickness and external or vessel lumen diameter over the 12-month period. Of those that demonstrated regression, the only predictor of percentage change in the LAD wall thickness was the baseline LAD wall thickness. Despite a favorable change in blood lipid profile, no overall change in the LAD wall thickness was detected over a 12-month period in subjects on moderate statin therapy using HRTTE. However, using case-based analysis, regression was able to be predicted by the baseline LAD wall thickness. HRTTE may be an instructive noninvasive modality to assess response to statin intervention.

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

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. 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. 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. Both pitavastatin and pravastatin altered coronary artery plaque composition by significantly decreasing the fibrofatty plaque component and increasing the calcified plaque component.

Prospective, randomized, single-blind comparison of effects of 6 months' treatment with atorvastatin versus pravastatin on leptin and angiogenic factors in patients with coronary artery disease

Leptin has been reported to exert an atherosclerotic effect by regulating expression of angiogenic factors that have been implicated in the pathogenesis of coronary artery disease (CAD). The purpose of this study was to investigate whether lipid-lowering therapy (LLT) with statins could affect leptin levels and angiogenic factors in patients with CAD. This study included 76 patients with CAD and 15 subjects without CAD (non-CAD). CAD patients were randomized to 6months of intensive LLT with atorvastatin or moderate LLT with pravastatin. Plasma leptin, angiopoetin-2 (Ang-2), hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF) levels were measured prior to statin therapy (baseline) and after 6months. Baseline levels of leptin, Ang-2, HGF and VEGF were higher in the CAD group than in the non-CAD group (all P<0.05). Treatment with intensive LLT decreased leptin, Ang-2, HGF and VEGF levels, whereas moderate LLT did not change these levels. This study suggests that LLT with atorvastatin decreases leptin levels and angiogenic factors in patients with CAD, possibly contributing to the beneficial effects of LLT with atorvastatin in CAD.

Reduction in Recurrent Cardiovascular Events With Intensive Lipid-Lowering Statin Therapy Compared With Moderate Lipid-Lowering Statin Therapy After Acute Coronary Syndromes: From the PROVE IT–TIMI 22 (Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis In Myocardial Infarction 22) Trial

In addition to reducing first events in patients after an acute coronary syndrome (ACS), we hypothesized that high-dose atorvastatin 80 mg would also reduce recurrent cardiovascular events, and therefore total events, compared with pravastatin 40 mg during the 2-year follow-up. In the PROVE IT-TIMI 22 (Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction 22) trial, more intensive lipid lowering with high-dose atorvastatin reduced the first occurrence of the primary end point (death, myocardial infarction, unstable angina requiring rehospitalization, stroke, or revascularization > or = 30 days) compared with moderate lipid lowering with pravastatin. Poisson regression analysis was performed to compare the number of occurrences of the primary end point between high-dose atorvastatin and pravastatin in the PROVE IT-TIMI 22 trial. As previously reported, first primary end point events were reduced by 16% with atorvastatin 80 mg versus pravastatin 40 mg (n = 464 vs. n = 537, respectively; p = 0.005). Additional events were also reduced by 19% with atorvastatin 80 mg (n = 275 vs. n = 340, respectively; p = 0.009). Overall, there were 138 fewer primary efficacy events with atorvastatin 80 mg versus pravastatin 40 mg (n = 739 vs. n = 877, respectively; rate ratio: 0.85, 95% confidence interval: 0.77 to 0.94, p = 0.001). Although analytic techniques commonly used in clinical outcomes trials censor patients who experience a component of the primary composite end point, total cardiovascular events are important to patients, clinicians, and health care payers. Maintaining low levels of low-density lipoprotein cholesterol is central to preventing additional atherosclerotic development and subsequent cardiovascular events. Atorvastatin 80 mg, a more intensive low-density lipoprotein cholesterol lowering agent, reduced both first and subsequent primary end point events compared with pravastatin 40 mg after ACS.

Aggressive lipid-lowering is more effective than moderate lipid-lowering treatment in carotid plaque stabilization

Atherosclerotic plaque stabilization is a promising strategy to prevent cerebrovascular events in patients with carotid atherosclerosis. Vascular calcification inhibitors, known osteopontin (OPN) and osteoprotegerin (OPG), have emerged as novel cardiovascular biomarkers. This open-label, prospective study aimed to examine whether aggressive lipid-lowering therapy with atorvastatin is more effective than moderate lipid-lowering in increasing carotid plaque echogenicity, assessed by Gray-Scale Median (GSM) score and suppressing serum OPN and OPG levels in patients with moderate carotid stenosis. One hundred forty patients (64 males, 76 females), aged 50 to 75 years, with carotid stenosis (North American Symptomatic Carotid Endarterectomy Trial [NASCET]: 30%-60% for symptomatic and 30%-70% for asymptomatic), but without indications for surgical intervention, were enrolled. Patients with coronary heart disease, renal failure, hypothyroidism, osteoporosis, and ongoing use of statins were excluded. Patients were randomly assigned to: Group A (N = 70): Moderate lipid-lowering therapy with low-dose of atorvastatin (10 mg-20 mg) to target LDL-C <100 mg/dL. Group B (N = 70): Aggressive lipid-lowering therapy with high-dose of atorvastatin (80 mg) to target LDL-C <70 mg/dL. Blood pressure, lipid and glycemic indexes, hsCRP, serum OPN, and OPG were measured at baseline and after 12 months as well as the GSM score. Independent samples t test, paired samples t test, Pearson correlation, and multiple regression analysis were used (P < .05). There were no significant differences between groups at baseline. Three patients in group A experienced either cerebrovascular or cardiac ischemic attacks, while two patients in group B underwent coronary angioplasty during follow-up. Group B showed a more pronounced improvement in total cholesterol and LDL-cholesterol compared with group A (P < .05). Moreover, atorvastatin treatment suppressed serum hsCRP, OPN, and OPG levels from baseline in both groups (P < .001). Notably, aggressive treatment decreased OPN (P = .012) and OPG (P = .025) levels to a greater degree compared with moderate treatment. Similarly, GSM score was remarkably increased in both groups, but that augmentation was greater in group B (from 66.39 +/- 23.66 to 100.4 +/- 25.31) than in group A (from 64.4 +/- 23.62 to 85.39 +/- 20.21) (P = .024). No change in the degree of carotid stenosis was noted in both treatment arms. Importantly, the aforementioned reduction in OPN (r = -0.517, P = .024) and OPG (r = -0.312, P = .008) levels was inversely associated with GSM score changes in univariate and standard multiple regression analysis (R(2) = 0.411, P = .021). Among patients with moderate carotid stenosis, an aggressive atorvastatin regimen enhanced carotid plaque echogenicity and reduced serum OPN and OPG levels to a greater extent than respective moderate atorvastatin therapy. Most importantly, those atorvastatin-induced effects were associated with OPN and OPG suppression in a dose-dependent manner.

Effect of intensive lipid-lowering therapy on telomere erosion in endothelial progenitor cells obtained from patients with coronary artery disease

Telomere erosion of EPCs (endothelial progenitor cells) may be a key factor in endothelial cell senescence and is highly dependent on cellular oxidative damage. The aim of the present study was to investigate whether LLT (lipid-lowering therapy) with statins could attenuate EPC telomere erosion in patients with CAD (coronary artery disease). The study included 100 patients with stable CAD and 25 subjects without CAD as controls. CAD patients were randomized to 12 months of intensive LLT with atorvastatin or moderate LLT with pravastatin. EPCs were obtained from peripheral blood at baseline and after 12 months of statin therapy. Telomere length in EPCs was measured by FISH (fluorescence in situ hybridization) and oxidative DNA damage by flow cytometry of oxidized DNA bases. EPC telomere length was shorter in the CAD group than in the controls, and oxidative DNA damage to EPCs was higher in the CAD group compared with controls. After 12 months of therapy, changes in lipid profiles were greater in the intensive LLT group than in the moderate LLT group. Intensive LLT markedly increased EPC number and decreased oxidative DNA damage in EPCs (both P<0.05), with no change in telomere length. In contrast, moderate LLT did not change EPC counts or oxidative DNA damage, but showed telomere shortening (P<0.05). There was a weak negative correlation between changes in EPC number and LDL (low-density lipoprotein)-cholesterol levels after intensive LLT, whereas there was no correlation between them after moderate LLT. With in vitro culturing of EPCs subjected to oxidative stress, atorvastatin led to the prevention of EPC telomere shortening compared with pravastatin. In conclusion, the present study has demonstrated that intensive LLT may prevent EPC telomere erosion in patients with CAD, possibly contributing to the beneficial effects of intensive LLT in this disorder.