The guidelines for cholesterol management have been updated over the years from treat-to-target using any drug class to emphasis on statins without treatment targets to a hybrid of the 2 approaches. The most recent guideline updates include newer nonstatin lipid-lowering therapies (LLTs), low-density lipoprotein cholesterol (LDL-C) reduction goals, and LDL-C thresholds considering secondary prevention and cardiovascular risk. Although statins have been the mainstay of LLT for years, newer pharmacological agents such as proprotein convertase subtilisin-kexin type 9 inhibitor(s) (PCSK9i) monoclonal antibodies, small interfering RNA PCSK9i, and bempedoic acid to optimize LDL-C levels may be underutilized in clinical practice. To provide an updated review for clinicians, we performed a literature search in PubMed for articles published from January 1, 2000, to August 31, 2023, that included the terms cholesterol, LLT, bempedoic acid, inclisiran, or PCSK9 inhibitor. Studies were selected for inclusion according to relatedness to cholesterol management and outcomes with novel LLT agents. Optimization of statins can improve the lipid profile and contribute to primary and secondary atherosclerotic cardiovascular disease (ASCVD) prevention. The newest guidance combines anticipated LDL-C reduction from statins and LDL-C thresholds for primary and secondary prevention. Nonstatin agents such as PCSK9i monoclonal antibodies, small interfering RNA PCSK9i, and bempedoic acid are safe and effective LLTs that can be used in addition to statin therapy for additional LDL-C lowering and prevention of ASCVD. Additionally, these nonstatin agents are reasonable to initiate in patients who have not been able to tolerate statins due to myalgias, rhabdomyolysis, or contraindications. Cost may be a barrier to initiating these agents for patients who are underinsured or uninsured. Clinicians should reference the most up-to-date guidance for LLT for primary and secondary prevention of ASCVD. Additionally, clinicians must diligently continue to optimize statin and nonstatin LLT to improve cardiovascular health outcomes.

We believe that there is sufficient evidence from basic science, longitudinal cohort studies and randomised controlled trials which validates the low-density lipoprotein cholesterol (LDL-C) or lipid hypothesis. It is important that we can communicate details of the cardiovascular disease (CVD) risk reduction that the average patient could expect depending on the scale of LDL-C decrease following lipid lowering therapy. It is also essential that residual risk (ResR) of CVD be highlighted. To achieve this aim by using existing trial evidence, we developed mathematical models initially for relative risk reduction (RRR) and absolute risk (AR) reduction and then showed that despite optimising LDL-C levels, a considerable degree of ResR remains that is dependent on AR. Age is significantly associated with AR (odds ratio: 1.02, 95% confidence intervals: 1.01-1.04) as was previously demonstrated by analysing the Whickham study cohort using a logistic regression model (age remaining significant even when all the other significant risk factors such as sex, smoking, systolic blood pressure, diabetes and family history were included in the regression model). A discussion of a paper by Ference et al. provided detailed evidence of the relationship between age and AR, based on lifetime LDL-C exposure. Finally, we discussed non-traditional CVD risk factors that may contribute to ResR based on randomised controlled trials investigating drugs improving inflammation, thrombosis, metabolic and endothelial status.

Alterations in lipid and lipoprotein metabolism are factors that trigger several negative metabolic complications. Hyperlipidemia is the starting point for the development of comorbidities of the cardiovascular system, such as atherosclerosis. The search for compounds that reduce high levels of total cholesterol and triglycerides has been widely reported in several publications in the literature. Phthalimide derivatives have been extensively researched with various biological actions. In this study we evaluated the antihyperlipidemic ability of three phthalimide derivatives (FGT-2, FGT-3 and FGT-4) on a model of obesity and insulin resistance in mice. The animals were submitted to a hyperlipid diet for 60 days. On the thirtieth day they were treated with phthalimides (20 mg/kg). The positive control group was treated with Simvastatin (20 mg/kg) and the negative control received only the carboxymethylcellulose vehicle. Biochemical and histological analyzes of all groups were analyzed. The animals treated with phthalimidic derivatives had a reduction in total cholesterol, low density and very low density lipoproteins (LDL-c and VLDL-c), triglycerides and fasting glycemia when compared to the negative control group. The treated animals also showed good results when analyzing the atherogenic indexes Castelli i and II and the ratio Triglycerides/HDL-c. In the oral glucose tolerance test and in the insulin tolerance test, animals treated with phthalimides were more sensitive to the action of the hormone regulating carbohydrate uptake. In the evaluation of the transaminases (AST/ALT), the animals of the group treated with phthalimides presented a lower elevation than the other groups of the experiment, the same observed with the uric acid evaluation. Histological analyzes were performed on liver, kidney, heart and pancreas samples. The groups treated with the compounds FGT-2 and FGT3 presented discrete alterations in the liver and kidney. FGT-4 did not present histological alterations for both tissues and the three phthalimide derivatives did not cause alterations in the other organs. These results suggest that the phthalimides tested can act as antihyperlipidemic agents and have a pleiotropic action, by acting also reducing glycemia in insulin resistance model mimicking diabetes mellitus type 2. These compounds may appear as a new approach in the treatment of obesity and complications, which are multifaceted.

Atherosclerosis and its fearsome complications represent the first cause of morbidity and mortality worldwide. Over the last two decades, several pieces of evidence have been accumulated, suggesting a central role of inflammation in atheroma development. High sensitivity C-reactive protein (hsCRP) is a well-established marker of cardiovascular (CV) disease; high levels of hsCRP have been associated with adverse CV outcome after acute coronary syndrome (ACS) and, despite some controversy, an active role for hsCRP in initiation and development of the atherosclerotic plaque has been also proposed. Randomized clinical trials focusing on hsCRP have been crucial in elucidating the anti-inflammatory effects of statin therapy. Thus, hsCRP has been progressively considered a real CV risk factor likewise to low-density lipoprotein cholesterol (LDL-C), expanding the concept of residual CV inflammatory risk. Subsequent research has been designed to investigate potential new targets of atherothrombotic protection. Despite the fact that the clinical usefulness of hsCRP is widely recognized, hsCRP may not represent the ideal target of specific anti-inflammatory therapies. Clinical investigations, therefore, have also focused on other inflammatory mediators, restricting hsCRP to an indicator rather than a therapeutic target. The aim of the present review is to provide an illustrative overview of the current knowledge of atherosclerosis and inflammation, highlighting the most representative clinical studies of lipid-lowering and antiinflammatory therapies focused on hsCRP in CV diseases.

The progression and pattern of coronary atherosclerosis in diabetes mellitus (DM) is different from non-DM, leading to a higher rate of vascular complications in DM.

This study aims to assess and compare the high-risk plaque characteristics in the culprit artery of DM and non-DM patients with acute coronary syndrome (ACS) using virtual histology intravascular ultrasound (VH-IVUS).

A total of 158 ACS patients were included, 63 of whom were known to have DM. IVUS analysis was done in the de novo target vessel and culprit lesion for which percutaneous coronary intervention was planned. Culprit lesions with a visual-estimate angiographic stenosis of <70% were excluded.

The mean age of patients was 52.4 ± 11.6 years. The study group comprised 82% men, 31% with hypertension, and 39.87% with DM. No significant difference was observed between the DM and non-DM groups in relation to quantitative IVUS parameters like lesion length, minimal lumen area, and plaque area. However, there was a significant difference in VH-IVUS parameters like higher necrotic core and dense calcium in the DM patients than in the non-DM patients (p < 0.01). The occurrence of VH-derived thin-cap fibroatheroma (VH-TCFA) in the culprit vessel was significantly higher in the DM group than in the non-DM group (25.3 vs. 5.2%; p < 0.01). Positive vessel-wall remodeling was noted in both groups without any significant difference (p = 0.74).

The DM patients had high-risk plaque composition features like a higher necrotic core, which is a marker of plaque vulnerability. Thus, aggressive medical therapy targeting vascular inflammation using high-dose statins would help in the stabilization of unstable plaque morphology and the reduction of major cardiovascular events.

Lipoprotein(a) [Lp(a)] is a low-density lipoprotein (LDL)-like particle that associates with major adverse cardiovascular events (MACE). We examined relationships between Lp(a) measurements and changes in coronary atheroma volume following long-term maximally-intensive statin therapy in coronary artery disease patients.

Study of coronary atheroma by intravascular ultrasound: Effect of Rosuvastatin Versus Atorvastatin (SATURN) used serial intravascular ultrasound measures of coronary atheroma volume in patients treated with rosuvastatin 40 mg or atorvastatin 80 mg for 24 months. Baseline and follow-up Lp(a) levels were measured in 915 of the 1039 SATURN participants, and were correlated with changes in percent atheroma volume (ΔPAV).

Mean age was 57.7 ± 8.6 years, 74% were men, 96% were Caucasian, with statin use prior to study enrolment occurring in 59.3% of participants. Baseline [median (IQR)] LDL-cholesterol (LDL-C) and measured Lp(a) levels (mg/dL) were 114 (99, 137) and 17.4 (7.6, 52.9) respectively; follow-up measures were 60 (47, 77), and 16.5 (6.7, 57.7) (change from baseline: p < 0.001, p = 0.31 respectively). At baseline, there were 676 patients with Lp(a) levels <50 mg/dL [median Lp(a) of 10.9 mg/dL], and 239 patients with Lp(a) levels ≥ 50 mg/dL [median Lp(a) of 83.2 mg/dL]. Quartiles of baseline and follow-up Lp(a) did not associate with ΔPAV. Irrespective of the achieved LDL-C (<vs. ≥70 mg/dL), neither baseline nor on-treatment (<vs. ≥median) Lp(a) levels significantly associated with ΔPAV. No significant differences were observed in ΔPAV in Lp(a) risers versus non-risers, nor in those patients with baseline or on-treatment Lp(a) levels <vs. > 50 mg/dL.

In coronary artery disease patients prescribed long-term maximally intensive statin therapy with low on-treatment LDL-C levels, measured Lp(a) levels (predominantly below the 50 mg/dL threshold) do not associate with coronary atheroma progression. Alternative biomarkers may thus associate with residual cardiovascular risk in such patients.

We assessed the long-term (>10 years) clinical course of patients with documented coronary lesions deemed nonsignificant according to fractional flow reserve (FFR) assessment and investigated whether the initial FFR value impacted on prognosis. From January 2000 to October 2003, all patients submitted to coronary angiography with FFR measurement were included in a single-center, prospective registry. Patients with an FFR value >0.80 were treated medically without revascularization. Major adverse cardiac events (MACE) (death, acute coronary syndrome (ACS), or coronary revascularization) were compared according to initial FFR value (absolute value and by category, ≤0.90 vs >0.90). Analyses were performed using a multivariable Cox model and propensity score matching. Among 257 patients (332 lesions) treated medically initially, 131 (51%, 143 lesions) had FFR ≤0.90 and 126 (49%, 189 lesions) >0.90. During follow-up (median duration, 11.6 years), 82 (31.9%) had a MACE, 38 (14.8%) died, 17 (6.6%) had ACS, 93 (36.2%) had repeat coronary angiography, and 27 (10.5%) had revascularization. There was no clinical, biologic or angiographic difference between patients with initial FFR value ≤0.90 versus >0.90. Adjusted Cox model showed no difference in relative risk of MACE, death, ACS, or revascularization. Coronary angiographies were numerically more frequent in patients with FFR ≤0.90, versus FFR >0.90. These findings were confirmed by propensity score-matched comparison. In patients with coronary narrowings left unrevascularized based on FFR, an FFR value between 0.80 and 0.90 has no impact on long-term outcome compared with those with FFR >0.90. In conclusion, patients with high FFR values should not be considered as having a lower risk of coronary event.

Statin-mediated low-density lipoprotein cholesterol (LDL-C) lowering fails to prevent more than half of cardiovascular events in clinical trials. Serial plaque imaging studies have highlighted the benefits of aggressive LDL-C lowering, with plaque regression evident in up to two-thirds of patients with achieved LDL-C levels <70 mg/dL. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors permit LDL-C-lowering by a further 54% to 75% in statin-treated patients. The impact of achieving very low LDL-C levels with PCSK9 inhibitors on coronary atherosclerosis has not been investigated.

To test the hypothesis that incremental LDL-C lowering with the PCSK9 inhibitor, evolocumab, will result in a significantly greater change from baseline in coronary atheroma volume than placebo in subjects receiving maximally tolerated statin therapy.

A phase 3, multicenter, double-blind, randomized, placebo-controlled trial evaluating the impact of evolocumab on coronary atheroma volume as assessed by serial coronary intravascular ultrasound at baseline in patients undergoing a clinically indicated coronary angiogram with angiographic evidence of coronary atheroma, and after 78 weeks of treatment. Subjects (n = 968) were randomized 1:1 into 2 groups to receive monthly either evolocumab 420 mg or placebo subcutaneous injections.

The GLAGOV trial will explore whether greater degrees of plaque regression are achievable with ultrahigh-intensity LDL-C lowering after combination statin-PCSK9 inhibitor therapy. GLAGOV will provide important mechanistic, safety, and efficacy data prior to the eagerly anticipated clinical outcomes trials testing the PCSK9 inhibitor hypothesis (www.clinicaltrials.gov identifier NCT01813422).

Diminishing yellow color, evaluated by coronary angioscopy, is associated with plaque stabilization and regression. Our aim was to assess the effect of aggressive lipid-lowering therapy with rosuvastatin on plaque regression and instability. Thirty-seven patients with stable angina or silent myocardial ischemia who planned to undergo elective percutaneous coronary intervention and had angioscopic yellow plaques of grade 2 or more were randomized to high-dose (group H, 20 mg/day, n = 18) or low-dose (group L, 2.5 mg/day, n = 19) rosuvastatin therapy for 48 weeks. Yellow plaque was graded on a 4-point scale of 0 (white) to 3 (bright yellow) by angioscopy, and plaque volume was determined by intravascular ultrasound for plaques with a length of 5 to 15 mm. Color and volume were assessed at baseline and after 48 weeks by the investigators blinded to the rosuvastatin dosage, and were compared between the 2 dosing groups. The level of low-density lipoprotein-cholesterol decreased from 130.3 ± 25.5 mg/dl to 61.7 ± 16.5 mg/dl (-50 ± 19%: high intensity) in group H (p <0.001) and from 130.9 ± 28.5 mg/dl to 89.7 ± 29.0 mg/dl (-30 ± 22%: moderate intensity) in group L (mean ± SD, p <0.001). The average color grade of yellow plaques decreased from 2.0 to 1.5 in group H (p <0.001) and from 2.0 to 1.6 in group L (p <0.001) after 48 weeks. Plaque volume decreased significantly in group H but not in group L. The percent change in plaque volume was significantly larger in group H than in group L (p = 0.005). In conclusion, both high-dose and low-dose rosuvastatin increased plaque stability. However, high-dose rosuvastatin was more effective than low-dose rosuvastatin in inducing plaque volume regression. Clinical Trial Registration No: UMIN-CTR, UMIN000003276.

The use of fibrates in the treatment of dyslipidaemia has changed significantly over recent years. Their role appeared clear at the start of this century. The Helsinki Heart Study and Veterans Affairs High-Density Cholesterol Intervention Trial suggested significant benefit, especially in patients with atherogenic dyslipidaemia. However, this clarity disintegrated following the negative outcomes reported by the Bezafibrate Infarction Prevention, Fenofibrate Intervention and Event Lowering in Diabetes and Action to Control Cardiovascular Risk in Diabetes randomised controlled trials. In this review we discuss these and other relevant trials and consider patient subgroups such as those with the metabolic syndrome and those needing treatment to prevent the microvascular complications associated with diabetes in whom fibrates may be useful. We also discuss observations from our group that may provide some explanation for the varying outcomes reported in large trials. The actions of fibrates in patients who are also on statins are interesting and appear to differ from those in patients not on statins. Understanding this is key as statins are the primary lipid lowering agents and likely to occupy that position for the foreseeable future. We also present other features of fibrate treatment we have observed in our clinical practice; changes in creatinine, liver function tests and the paradoxical high density lipoprotein reduction. Our purpose is to provide enough data for the reader to make objective decisions in their own clinical practice regarding fibrate use.

Intravascular ultrasound has been established as the gold standard for analyzing alterations in coronary artery atherosclerosis during monitoring investigations. Cross-sectional imaging can be used to visualize the area of the lumen and the vessel size and the plaque size as the difference between them. New technology allows the 3-D reconstruction of the volume for prespecified vessel segments using specific algorithms. Investigations on the natural course demonstrated predominantly progression. Even regression of coronary atherosclerosis can be visualized and quantified. Regression can only be expected when the level of low-density lipoprotein (LDL) cholesterol is below the critical level of 75 mg/dl. Prospective randomized studies with highly effective statins showed that regression occurred in up to two thirds of patients when LDL cholesterol was below a cut-off of 78 mg/dl and was, therefore, very close to the threshold, which was calculated based on investigations of the natural course. Although the absolute values for plaque volume are in the range of 1 % over 1-2 years, it must be taken into consideration that coronary artery diseases are chronic diseases and a 1 % change per year will correspond to an enormous effect on plaque growth of coronary vessels. The great success of statins in reducing cardiovascular events is due to the possibility for reduction of progression and induction of regression. New developments in medication will be measured against the effectiveness of statins.

Statins have been shown to possess favourable effects on the cardiovascular system with stabilization of the vulnerable plaque. We sought to assess the effects of early aggressive statin treatment on plaque composition in patients with acute myocardial infarction (AMI), using serial assessment with coronary CT-angiography (CTA).

In a prospective randomized blinded endpoint trial patients with AMI were randomized to an intensive lipid lowering treatment receiving statin loading with 80 mg rosuvastatin followed by 40 mg daily or standard statin therapy according to current guidelines. Patients were assessed with CTA at baseline and after 12 months with evaluation of plaque volume and composition.

In total, 140 patients with AMI were randomized and plaque composition was assessed in 96 patients. In the intensive care group LDL-level was median 1.3 [0.9; 1.5] mmol/l at 12 months follow-up and 2.0 [1.7; 2.4] mmol/l in the usual care group, p < 0.001. Plaque volume increased over 12 months with 43.5 (±225.8) mm(3) in the intensive care group and 19.1 (±190.2) mm(3) in the usual care group, p = 0.57. Plaque composition changed over 12 months with an increase in total dense calcium volume by 11.1 (±39.6) mm(3), corresponding to a 23% increase, in the intensive care group and a decreased by -0.4 (±26.6) mm(3) in the usual care group, p < 0.001. Necrotic core volume increased 26.8 (±122.1) mm(3) in the intensive care group and 25.2 (±80.1) mm(3) in the usual care group, p = 0.94.

Early aggressive lipid lowering therapy significantly increases dense calcium volume in patients with AMI.

Although statins can induce coronary atheroma regression, this benefit has yet to be demonstrated in diabetic individuals. We tested the hypothesis that high-intensity statin therapy may promote coronary atheroma regression in patients with diabetes.

The Study of Coronary Atheroma by Intravascular Ultrasound: Effect of Rosuvastatin Versus Atorvastatin (SATURN) used serial intravascular ultrasound measures of coronary atheroma volume in patients treated with rosuvastatin 40 mg or atorvastatin 80 mg for 24 months. This analysis compared changes in biochemistry and coronary percent atheroma volume (PAV) in patients with (n = 159) and without (n = 880) diabetes.

At baseline, patients with diabetes had lower LDL cholesterol (LDL-C) and HDL cholesterol (HDL-C) levels but higher triglyceride and CRP levels compared with patients without diabetes. At follow-up, diabetic patients had lower levels of LDL-C (61.0 ± 20.5 vs. 66.4 ± 22.9 mg/dL, P = 0.01) and HDL-C (46.3 ± 10.6 vs. 49.9 ± 12.0 mg/dL, P < 0.001) but higher levels of triglycerides (127.6 [98.8, 163.0] vs. 113.0 mg/dL [87.6, 151.9], P = 0.001) and CRP (1.4 [0.7, 3.3] vs. 1.0 [0.5, 2.1] mg/L, P = 0.001). Both patients with and without diabetes demonstrated regression of coronary atheroma as measured by change in PAV (-0.83 ± 0.13 vs. -1.15 ± 0.13%, P = 0.08). PAV regression was less in diabetic compared with nondiabetic patients when on-treatment LDL-C levels were >70 mg/dL (-0.31 ± 0.23 vs. -1.01 ± 0.21%, P = 0.03) but similar when LDL-C levels were ≤70 mg/dL (-1.09 ± 0.16 vs. -1.24 ± 0.16%, P = 0.50).

High-intensity statin therapy alters the progressive nature of diabetic coronary atherosclerosis, yielding regression of disease in diabetic and nondiabetic patients.

It is well recognized that low-density lipoprotein cholesterol (LDL-C)-lowering therapy is effective for primary and secondary prevention of cerebrovascular/cardiovascular disease. Ezetimibe, an inhibitor of the Niemann-Pick C1-Like 1 cholesterol transporter, is a relatively new drug for LDL-C-lowering therapy in addition to statins. However, comparison between an aggressive LDL-C-lowering therapy with a combination of statin and ezetimibe versus a standard LDL-C-lowering therapy with statin alone is still unclear in terms of their effects on stabilization and volume regression of coronary plaque. The ZIPANGU (Ezetimibe clinical investigation for the regression of intracoronary plaque evaluated by angioscopy and ultrasound) study is aimed at comparing these two types of therapy based on indices of plaque characteristics using non-obstructive coronary angioscopy and intravascular ultrasound.

The study is a multi-center, prospective, randomized, open-label, blinded-endpoint trial. Through a centralized enrollment method, patients will be allocated to either monotherapy with atorvastatin alone or to combination therapy with atorvastatin (maximum: 20mg/day) and ezetimibe (10mg/day). The target LDL-C level will be <100mg/dL for the monotherapy group and <70mg/dL for the combination therapy group. At the baseline and the follow-up period of 9 months, non-obstructive coronary angioscopy and intravascular ultrasound will be performed to compare the changes in plaque color and volume between the two groups.

The ZIPANGU study will clarify whether combination therapy with statins and ezetimibe is better for stabilizing coronary plaque as secondary prevention than monotherapy by statins alone. The study will give new insights into lipid-lowering guidelines in Japan.

Carotid atheromatous disease is an important cause of stroke and represents a key target in stroke prevention. Randomized trials have shown the efficacy of carotid endarterectomy in secondary stroke prevention. Carotid stenting presents a less invasive alternative to surgical intervention. Advances in medical management, if compliance can be ensured, are leading to improvement in outcomes when implemented as sole therapy in the treatment of atherosclerotic carotid stenosis. This includes lifestyle modification, blood pressure control, and antiplatelet and statin therapy. Over the last 20 years, the annual rate of ipsilateral stroke associated with asymptomatic carotid stenosis has decreased from 2% to 4% to less than 1%. This is largely due to improvements in medical therapy. However, despite numerous trials and years of clinical research, the optimal management of symptomatic and asymptomatic carotid disease remains controversial. This article presents and summarizes the evidence supporting best medical treatment for carotid artery stenosis.

Intravascular ultrasonography (IVUS) and (18)F-FDG PET have been used to evaluate the efficacy of antiatherosclerosis drugs. These two modalities image different characteristics of atherosclerotic plaques, and a comparison of IVUS and PET images with histology has not been performed. The aim of this study was to align IVUS and PET images using anatomic landmarks in Watanabe heritable hyperlipidaemic (WHHL) rabbits, enabling comparison of their depiction of aortic atherosclerosis. Cellular (18)F-FDG localization was evaluated by (3)H-FDG microautoradiography (micro-ARG).

A total of 19 WHHL rabbits (7 months of age) were divided into three groups: baseline (n = 6), 3 months (n = 4), and 6 months (n = 9). PET, IVUS and histological images of the same aortic segments were analysed. Infiltration by foamy macrophages was scored from 0 to IV using haematoxylin and eosin (H&E) and antimacrophage immunohistochemical staining, and compared with (3)H-FDG micro-ARG findings in two additional WHHL rabbits.

IVUS images did not identify foamy macrophage deposition but revealed the area of intimal lesions (r = 0.87). (18)F-FDG PET revealed foamy macrophage distribution in the plaques. The intensity of (18)F-FDG uptake was correlated positively with the degree of foamy macrophage infiltration. Micro-ARG showed identical (3)H-FDG accumulation in the foamy macrophages surrounding the lipid core of the plaques.

F-FDG PET localized and quantified the degree of infiltration of foamy macrophages in atherosclerotic lesions. IVUS defined the size of lesions. (18)F-FDG PET is a promising imaging technique for evaluating atherosclerosis and for monitoring changes in the composition of atherosclerotic plaques affecting their stability.

To investigate the liver cellular apoptosis in response to burn injury and find out if statin treatment can ameliorate this process. The hypothesis is that statin may modulate apoptosis-related gene expression and thereby reduce hepatocytic apoptosis after burn injury.

Mice were subjected to 30% full-thickness burn injury and then treated either with or without simvastatin. The livers were harvested for histological assessment and determinations of gene expression. To investigate the mechanism involved, tumor necrosis factor (TNF)-α and caspase-3 knockout (KO) mice were also used to evaluate the effects of burn injury and simvastatin treatment on burn-induced liver injury. The effects of simvastatin on TNF-α and caspase-3 expressions were also evaluated in cultured mouse hepatocytes.

Burn injury induced significant liver damage, which was indicated by striking levels of apoptosis. Simvastatin reduced the apoptotic index in the livers of mice with burn injury and this effect could be abrogated by TNF-α or caspase-3 inhibitors. Simvastatin also decreased burn-induced TNF-α and caspase-3 expression in the liver. TNF-α and caspase-3 KO mice demonstrated lower levels of apoptotic hepatocytes in response to burn, and simvastatin did not further decrease hepatocyte apoptosis in either strain of KO mice. An in vitro study demonstrated that simvastatin suppresses TNF-α and caspase-3 expression in primary cultures of mouse hepatocytes.

Simvastatin reduces mouse hepatocyte apoptosis by suppressing expression of the TNF-α/caspase-3 pathway.

Early high-dose statin therapy to reduce low-density lipoprotein cholesterol (LDL-C) is associated with improved cardiovascular outcomes in Western patients with stable coronary heart disease or acute coronary syndromes (ACS), but many patients remain undertreated and do not attain LDL-C treatment goals. Early statin therapy has also been shown to improve cardiovascular outcomes in Japanese patients with ACS, and pretreatment with high-dose statin prior to percutaneous coronary intervention has been shown to reduce cardiovascular events in these patients. As is the case in Western populations, many Japanese patients may be undertreated and a residual cardiovascular risk remains. While differences in treatment practice, dosing and genetic factors exist between Japan and Western countries, similarities are also evident when Japanese statin studies are compared with those performed in Western populations. With the increasing prevalence of cardiovascular risk factors in Japan, aggressive statin treatment may be beneficial in achieving optimal cardiovascular outcomes.

To compare the therapeutic effects of intensive versus moderate dosage of atorvastatin regimens in new-onset unstable angina with borderline lesions, 100 patients were randomized to receive either 80 mg/d or 20 mg/d atorvastatin for 9 months. Clinical symptoms, lipid profiles, and coronary stenosis (evaluated by coronary angiography and intravascular ultrasound) were compared to their corresponding baselines within each group and between the 2 groups after 9 months of treatment. The results showed that (1) when compared to their corresponding baselines, both groups exhibited improvement in clinical symptoms, a significant decrease in total cholesterol, triglyceride, low-density lipoprotein cholesterol (LDL-C), and high-sensitivity C-reactive protein (hs-CRP; P < .01) and a significant increase in high-density lipoprotein cholesterol (HDL-C); (2) the improvement in clinical symptoms and the decrease in LDL-C and hs-CRP were significantly greater (P < .01) in the intensive-dose group than in the moderate-dose group; (3) the mean plaque volume did not progress in the intensive-dose group but increased significantly (P < .05) in the moderate-dose group. We conclude that compared to the moderate dose, the intensive-dose regimen significantly improves clinical symptoms, lowers LDL-C and hs-CRP, and halts the progression of borderline atherosclerotic plaques in patients with new-onset unstable angina.

Angiogenesis is induced from sprouting of preexisting endothelial cells leading to neovascularization. Imbalance in the angiogenic and antiangiogenic mediators triggers angiogenesis, which may be physiological in the normal state or pathological in malignancy and atherosclerosis. Physiologic angiogenesis is instrumental for restoration of vessel wall normoxia and resolution inflammation, leading to atherosclerosis regression. However, pathological angiogenesis enhances disease progression, increasing macrophage infiltration and vessel wall thickness, perpetuating hypoxia and necrosis. In addition, thin-walled fragile neovessels may rupture, leading to intraplaque hemorrhage. Lipid-rich red blood cell membranes and free hemoglobin are detrimental to plaque composition, increasing inflammation, lipid core expansion, and oxidative stress. In addition, associated risk factors that include polymorphysms in the haptoglobin genotype and diabetes mellitus may modulate the features of plaque vulnerability. This review will focus on physiological and pathological angiogenesis in atherosclerosis and summarizes the current status of anti-vascular endothelial growth factor (VEGF) therapy, microvascular rarefaction, and possible statin-mediated effects in atherosclerosis neovascularization.

GH replacement therapy (GHRT) in adult-onset GH deficiency (AOGHD) reduces carotid intima-media thickness (IMT) and increases myocardial mass, with improvement of systolic and diastolic function. These observations have reinforced the use of GHRT on AOGHD. Conversely, we have previously reported that in adults with lifetime congenital and severe isolated GH deficiency (IGHD) due to a mutation in GHRH receptor gene (GHRHR), a 6-month treatment with depot GH increased carotid IMT, caused the development of atherosclerotic plaques, and an increase in left ventricular mass index (LVMI), posterior wall, and septal thickness and ejection fraction. Such effects persisted 12 months after treatment (12-month washout - 12 mo).

We have studied the cardiovascular status (by echocardiography and carotid ultrasonography) of these subjects 60 months after completion of therapy (60-month washout - 60 mo).

Carotid IMT reduced significantly from 12 to 60 mo, returning to baseline (pre-therapy) value. The number of individuals with plaques was similar at 12 and 60 mo, remaining higher than pre-therapy. LVMI, relative posterior wall thickness, and septum thickness did not change between 12 and 60 mo, but absolute posterior wall increased from 12 to 60 mo. Systolic function, evaluated by ejection fraction and shortening fraction, was reduced at 60 mo in comparison with 12 mo returning to baseline levels. The E/A wave ratio (expression of diastolic function) decreased at 60 mo compared with both 12 mo and baseline.

In adults with lifetime congenital IGHD, the increase in carotid IMT elicited by GHRT was transitory and returned to baseline 5 years after therapy discontinuation. Despite this, the number of subjects with plaques remained stable at 60 mo and higher than at baseline.

With the rising global incidence of cardiovascular disease, the challenge for the pharmaceutical industry is to identify novel biomarkers that will allow not only for the development of the next generation of cardiometabolic therapeutics, but also to serve as a sensitive mechanism to monitor and predict drug efficacy and potential toxicity. The advent of an 'omics' (systems biological) approach has vast implications for future disease treatment and prevention. Lipidomics is the latest addition to the 'omics' family and is rapidly gaining attention due to the technological improvements in mass spectrometry, allowing for the characterization of large number of lipids (and their respective subclasses) in a short amount of time with relatively minimal preparation.

The authors discuss the various techniques involved in plasma lipidomics as well as outline the role that lipidomics will play in phenotyping disease processes and corresponding therapeutic strategies. The article was formed through comprehensive Medline search of relevant publications in this area.

Despite the wealth of data that will emerge regarding the various lipid-molecular interactions and the functions of lipids within cells, a major challenge will be the parallel emergence of novel bioinformatics platforms in order to integrate this enormous data set with information generated from the emerging fields of genomics and proteomic analysis. Despite these challenges, lipidomics is likely to result in the reclassification of diseases from a molecular perspective and play a key role the eventuation of personalized medicine.

Statins reduce adverse cardiovascular outcomes and slow the progression of coronary atherosclerosis in proportion to their ability to reduce low-density lipoprotein (LDL) cholesterol. However, few studies have either assessed the ability of intensive statin treatments to achieve disease regression or compared alternative approaches to maximal statin administration.

We performed serial intravascular ultrasonography in 1039 patients with coronary disease, at baseline and after 104 weeks of treatment with either atorvastatin, 80 mg daily, or rosuvastatin, 40 mg daily, to compare the effect of these two intensive statin regimens on the progression of coronary atherosclerosis, as well as to assess their safety and side-effect profiles.

After 104 weeks of therapy, the rosuvastatin group had lower levels of LDL cholesterol than the atorvastatin group (62.6 vs. 70.2 mg per deciliter [1.62 vs. 1.82 mmol per liter], P<0.001), and higher levels of high-density lipoprotein (HDL) cholesterol (50.4 vs. 48.6 mg per deciliter [1.30 vs. 1.26 mmol per liter], P=0.01). The primary efficacy end point, percent atheroma volume (PAV), decreased by 0.99% (95% confidence interval [CI], -1.19 to -0.63) with atorvastatin and by 1.22% (95% CI, -1.52 to -0.90) with rosuvastatin (P=0.17). The effect on the secondary efficacy end point, normalized total atheroma volume (TAV), was more favorable with rosuvastatin than with atorvastatin: -6.39 mm(3) (95% CI, -7.52 to -5.12), as compared with -4.42 mm(3) (95% CI, -5.98 to -3.26) (P=0.01). Both agents induced regression in the majority of patients: 63.2% with atorvastatin and 68.5% with rosuvastatin for PAV (P=0.07) and 64.7% and 71.3%, respectively, for TAV (P=0.02). Both agents had acceptable side-effect profiles, with a low incidence of laboratory abnormalities and cardiovascular events.

Maximal doses of rosuvastatin and atorvastatin resulted in significant regression of coronary atherosclerosis. Despite the lower level of LDL cholesterol and the higher level of HDL cholesterol achieved with rosuvastatin, a similar degree of regression of PAV was observed in the two treatment groups. (Funded by AstraZeneca Pharmaceuticals; ClinicalTrials.gov number, NCT000620542.).

Pharmacological studies with drugs that activate or inhibit several protein kinase C (PKC) isozymes have identified the PKC family of serine-threonine kinases as important in the regulation of gamma-aminobutyric acid type A (GABA(A)) receptor function. PKC modulates GABA(A) receptor surface density, chloride conductance and receptor sensitivity to positive allosteric modulators such as neurosteroids, ethanol, benzodiazepines and barbiturates. Recent studies using PKC isozyme-selective reagents and gene-targeted mice have begun to identify critical roles for three isozymes, PKCbetaII, PKCvarepsilon and PKCgamma, in various aspects of GABA(A) receptor regulation. Progress in this field touches upon therapeutic areas that are of great clinical importance such as anxiety and addiction. Increased understanding of how PKC regulates GABA(A) receptors and which PKC isozymes are involved holds promise for development of new treatments for diverse neuropsychiatric disorders.