New targets, treatments and trials for preventing and reversing atherosclerosis: the paradox of choice No abstract available

SPPARM alpha: the Lazarus effect Purpose of review Atherogenic dyslipidaemia, characterized by high plasma triglycerides (a surrogate for triglyceride-rich remnant lipoproteins) and low high-density lipoprotein cholesterol (HDL-C), is prevalent in patients with type 2 diabetes mellitus (T2DM) and contributes to a high modifiable residual cardiovascular risk. Fibrates are effective in managing hypertriglyceridaemia but lack consistent cardiovascular benefit in clinical trials and exhibit pharmacokinetic interaction with statins (gemfibrozil) and renal and hepatic safety issues (fenofibrate). The selective peroxisome proliferator-activated receptor alpha modulator (SPPARMα) paradigm offers potential for improving potency, selectivity and the benefit-risk profile. Recent findings The present review discusses evidence for the novel SPPARMα agonist, pemafibrate. Clinical trials showed robust lowering of triglyceride-rich lipoproteins, elevation in HDL-C and nonlipid beneficial effects including anti-inflammatory activity. There was a favourable safety profile, with no increase in serum creatinine, evident with fenofibrate, and improved renal and hepatic safety. The cardiovascular outcomes study PROMINENT is critical to confirming the SPPARMα concept by validating reduction in residual cardiovascular risk in patients with T2DM and long-term safety. Summary SPPARMα offers a new paradigm for reducing residual cardiovascular risk in T2DM. PROMINENT will be critical to differentiating the first SPPARMα, pemafibrate, as a novel therapeutic class distinct from current fibrates.

Proprotein convertase subtilisin/kexin type 9 inhibitors and lipoprotein(a)-mediated risk of atherosclerotic cardiovascular disease: more than meets the eye? Purpose of review Evidence continues to mount for elevated lipoprotein(a) [Lp(a)] as a prevalent, independent, and causal risk factor for atherosclerotic cardiovascular disease. However, the effects of existing lipid-lowering therapies on Lp(a) are comparatively modest and are not specific to Lp(a). Consequently, evidence that Lp(a)-lowering confers a cardiovascular benefit is lacking. Large-scale cardiovascular outcome trials (CVOTs) of inhibitory mAbs targeting proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) may address this issue. Recent findings Although the ability of PCSK9i to lower Lp(a) by 15–30% is now clear, the mechanisms involved continue to be debated, with in-vitro and in-vivo studies showing effects on Lp(a) clearance (through the LDL receptor or other receptors) and Lp(a)/apolipoprotein(a) biosynthesis in hepatocytes. The FOURIER CVOT showed that patients with higher baseline levels of Lp(a) derived greater benefit from evolocumab and those with the lowest combined achieved Lp(a) and LDL-cholesterol (LDL-C) had the lowest event rate. Meta-analysis of ten phase 3 trials of alirocumab came to qualitatively similar conclusions concerning achieved Lp(a) levels, although an effect independent of LDL-C lowering could not be demonstrated. Summary Although it is not possible to conclude that PCSK9i specifically lower Lp(a)-attributable risk, patients with elevated Lp(a) could derive incremental benefit from PCSK9i therapy.

Strategies to alter the trajectory of atherosclerotic cardiovascular disease Purpose of review Cardiovascular disease prevention trials of lipid lowering with statins have shown unexpected long-term benefits after the formal randomized treatment stopped. This finding needs further exploration because it raises the possibility that the trajectory of the disease can be modified. Recent findings Extended follow up data are now available from further major primary prevention studies and from meta-analyses of the legacy effect of statin trials. New outcome studies have been proposed and launched to test the ability of early intervention to slow or regress atherosclerosis. Summary Legacy effects are apparent in trials of LDL lowering in hypercholesterolemic and hypertensive patient cohorts. Over follow up periods of decades, both cardiovascular mortality and all-cause mortality are reduced in individuals who received 3 to 5 years of statin therapy. The phenomenon is observed also in studies of intensive glycemic control suggesting that it is possible to impact plaque development with long-term beneficial consequences. Novel strategies for primary prevention are being devised that include the early use of both prolonged-moderate and short-term aggressive LDL lowering.

Implications of serial coronary computed tomography angiography in the evaluation of coronary plaque progression Purpose of review The purpose is to review the use of coronary computed tomography (CT) angiography to assess coronary plaque burden/progression and to discuss about recent clinical trials that have utilized this imaging modality to study the effect of new pharmacotherapies on plaque burden/progression. Recent findings There are numerous clinical trials that have utilized coronary CT angiography to demonstrate the potential benefits of statins, apixaban, rivaroxaban, aged garlic extract, biologic agents, and omega-3 fatty acids to reduce coronary plaque progression. Coronary CT angiography can identify high-risk plaques and can also quantify total plaque burden, both of which are independent risk factors to predict major adverse cardiac events. Summary Coronary heart disease remains one of the leading cause of mortality in the world. Utilizing coronary CT angiography, it is possible to identify rupture-prone plaques and also to quantify the total plaque burden. New pharmacotherapies that have the potential to reduce plaque progression have been used in clinical trials and these trials have utilized coronary CT angiography to track coronary atheroma progression. In future, we will see frequent utilization of coronary CT angiography to track coronary atheroma.

Is proteomics of value in cardiovascular risk assessment? Purpose of review To briefly summarize recently published evidence in the field of cardiovascular proteomics, focusing on its ability to improve cardiovascular risk stratification and critically discussing still open and burning issues and future perspectives of proteomics research. Recent findings Several epidemiological studies have demonstrated an improvement in cardiovascular risk prediction beyond traditional risk factors by adding novel biomarkers, identified by both discovery and targeted proteomics. However, only a moderate improvement in risk discrimination over clinical variables was observed. Moreover, despite different outcomes there was also a strong overlap of identified candidates, with several of them being already well established cardiovascular risk markers such as growth differentiation factor 15, natriuretic peptides, C-reactive protein, interleukins, and metalloproteases. Summary Although proteomics plays a crucial role in biomarker discovery, the modest discriminative ability of this technique raises the possibility that there are still hidden mechanisms in protein regulatory networks, which urgently need to be evaluated to improve a cardiovascular risk assessment to a clinically significant extent.

Cholesterol membrane content has a ubiquitous evolutionary function in immune cell activation: the role of HDL Purpose of review Cellular cholesterol content influences the structure and function of lipid rafts, plasma membrane microdomains essential for cell signaling and activation. HDL modulate cellular cholesterol efflux, thus limiting cholesterol accumulation and controlling immune cell activation. Aim of this review is to discuss the link between HDL and cellular cholesterol metabolism in immune cells and the therapeutic potential of targeting cholesterol removal from cell membranes. Recent findings The inverse relationship between HDL-cholesterol (HDL-C) levels and the risk of cardiovascular disease has been recently challenged by observations linking elevated levels of HDL-C with increased risk of all-cause mortality, infections and autoimmune diseases, paralleled by the failure of clinical trials with HDL-C-raising therapies. These findings suggest that improving HDL function might be more important than merely raising HDL-C levels. New approaches aimed at increasing the ability of HDL to remove cellular cholesterol have been assessed for their effect on immune cells, and the results have suggested that this could be a new effective approach. Summary Cholesterol removal from plasma membrane by different means affects the activity of immune cells, suggesting that approaches aimed at increasing the ability of HDL to mobilize cholesterol from cells would represent the next step in HDL biology.

Lipid management in people with peripheral artery disease Purpose of review To summarize recent data on the role of dyslipidaemia and the benefit from managing this in people with disease of the abdominal aorta and its peripheral branches (peripheral artery disease, PAD). Recent findings Findings from the Further Cardiovascular Outcomes Research with Proprotein convertase subtilisin/kexin type 9 (PCSK9) Inhibition in Subjects with Elevated Risk (FOURIER) trial demonstrate the benefit of intensely lowering low-density lipoprotein-cholesterol (LDL-c) in people with PAD to substantially reduce the incidence of major cardiovascular events (MACE; myocardial infarction, stroke or cardiovascular death) and major adverse limb events (MALE). Despite the evidence of substantial benefits from lowering LDL-c, the uptake of drug therapies to lower LDL-c remains sub-optimal in people with PAD. Summary Effective methods to educate physicians and patients on best medical management are needed. Further research is needed to examine the benefit of LDL-c lowering and other lipid therapies for PAD-specific problems like abdominal aortic aneurysm progression and walking impairment. Other novel lipid therapies, such as those that lower lipoprotein (a), maybe particularly beneficial to people with PAD given the evidence indicating high concentrations in this population and the high incidence of MACE in these individuals.

Can atherosclerosis be cured? Purpose of review Determine if evidence supports interventions to prevent development of atherosclerosis and atherosclerotic cardiovascular disease (ASCVD) events and death. Recent findings An extensive body of evidence supports the fundamental causal role of apolipoprotein B lipoproteins in the development of atherosclerosis. Recent epidemiologic studies have shown that LDL-cholesterol (LDL-C) and non-HDL-cholesterol levels in early adults are associated with accelerated subclinical atherosclerosis and an excess of atherosclerotic cardiovascular events later in life. Animal and human data have shown that intensive LDL-C lowering can regress earlier stages of atherosclerosis. Summary The next research priority is evaluating the impact of lowering LDL-C earlier in life to regress early atherosclerosis, followed by trials to demonstrate this approach will eradicate later-life ASCVD events and death. This approach of curing atherosclerosis will likely be the most effective strategy for reducing the huge global burden of atherosclerosis.