Potential therapies for promoting plaque regression
Various targets have been proposed to induce plaque regression or slow down the atherosclerosis process. Some potential therapeutic targets are discussed in the following paragraphs within the idea of plaque regression (Table 2).
Evidence of plaque regression
The plaque regression concept was evidenced earlier from animal studies 101 and from patients undergoing medical therapy 102, 103. Murine apo E−/− or the LDL receptor−/− suggested that plaque regression occurs 104. Plaque regression is an important therapeutic target. However, no extensive investigational evidence shows that plaque regression can be accomplished for advanced lesions 101. Transplantation using a segment of the plaque-containing aorta from hyperlipidemic apo E−/− mouse helped to investigate features regressing plaque 65. In vivo data demonstrated a rapid loss of foam cells from premature lesions within 3 days post-transplantation 105, 106. Yet, a great challenge was the finding of an atherosclerosis model of spontaneous plaque rupture with humanized endpoints such as MI, stroke, and unexpected death. Recently, these features are proposed in apo E-/-Fbn1C1039G+/- mice 107, 108. This model could evaluate the potential plaque stabilizing therapies to better define systemic antiatherosclerosis factors and their mechanisms.
Lipid-lowering therapy
Administration of hypolipidemic and antioxidant drugs were proposed to prevent the progress of atherosclerosis. Numerous clinical trials highlighted the role of statins 109. Moderate-or intensive statins therapy reduces LDL cholesterol (LDL-C) 110, promote atheroma stabilization 111, and induces coronary plaque volume regression 12, 103, 109. Statin therapy also reduces fibro-fatty components and increases dense calcium volume in atheromatic plaque 112. Statin was also associated with reduced IP angiogenesis in the carotid arteries 113. SATURN trial showed that more than 60% of rosuvastatin or atorvastatin-treated patients showed plaque regression 112, 114. Therefore, statins may not affect the instability features of the plaque as reported by meta-analysis studies 12. Unfortunately, atherosclerosis continues to progress in up to one-third of patients despite high statin treatment 115. This reinforces the need to reduce “residual risk” of coronary events 115, 116.
Anacetrapib
The use of anacetrapib in a patient with atherosclerosis and under intense statin therapy resulted in a lower incidence of major coronary events than the use of placebo (ClinicalTrials.gov number, NCT01252953) (Table 2). Anacetrapib trials showed reduction in plaque progression (mostly by decreasing non-high-density lipoprotein cholesterol HDL-C) and improvement of plaque stability 117. Of importance imaging studies are expected to evaluate this finding 118.
Antibody technology against PCSK9
Recent therapeutic advances have been reported using ezetimibe and humanized monoclonal antibody technology against PCSK9 118. Ezetimibe favour cholesterol absorption inhibition ameliorates endothelial dysfunction and atherosclerosis regression in coronary arteries 119. Results from the ZIPANGU study in patients with stable cardiovascular disease (CVD) suggested that ezetimibe and atorvastatin are more effective on plaque regression than statin alone 120. The GLAGOV trial was the first to compare combination therapy with statin plus evolocumab (named also Repatha) to statin therapy alone 121. In this study, Evolocumab induces atheroma regression (Table 2). Furthermore, Alirocumab (named also Praluent) and Evolocumab, have recently been accepted for the treatment of familial and nonfamilial hypercholesterolemia 122, 123. However, more studies in demand to assess the effects of PCSK9 inhibition on clinical consequences.
Potential novel molecular targets and current perspectives
Activation of macrophage inflammasomes releases interleukin (IL)-1β and IL-18 and promotes atherosclerosis and its complications in vivo 124. Inflammasome stimulation may contribute to atherosclerotic plaque erosion and thrombosis, exclusively in subjects having CVD risk as type 2 diabetes or chronic kidney disease 125. This finding received a solid support by targeting inflammatory pathway with a monoclonal antibody inhibiting interleukin-1β (IL-1β) named also canakinumab (Table 2). Blocking IL-1β may directly affect vascular atherosclerotic disease evolution 126, 127. However, in phase II trial benefits of canakinumab on plaque inflammation were not detected 126. The outcomes of this Phase II trial are proposed to be addressed by the multinational Phase III trial (CANTOS). Unfortunately, in a recent press release, the FDA declined to approve canakinumab for cardiovascular risk reduction from the CANTOS trial 128. While the CANTOS suggests a favorable profile for inflammasome-derived IL-1β in CVD, the magnitude of the advantage was moderate, and there was an excess of infections associated with this therapy 129, perhaps due to decreased neutrophil levels 125. Recent progress in this field proposes that molecules upstream of IL-1β secretion, such as NLRP3, caspase-1/11, or CMPK2, may provide further therapeutic targets for preventing atherosclerotic vascular disease 125, 130. Another therapy for plaque stability is exploring vascular growth factor angiopoietin-2 (Ang-2) 31.Ang-2 activity might play a role in the progress of unstable plaque 131. Ang-2 blockage was associated with decrease in triglyceride levels in plasma and fatty streak formation in hypercholesterolemic mice 2, 132. These results suggest a favorable drugability and safety index for the clinical use of antibodies inhibiting Ang-2 activity (Table. 2). Furthermore, the anti-inflammatory drugs that impair efferocytosis 133 may present new weapons to slow down the progression and development of CVD, while the detailed mechanisms are unclear 9.
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Probucol
Probucol is a powerful anti-oxidant with anti-hyperlipidemic activity 134 (Table 2). This drug is thought to stabilize plaques at high risk, perhaps via various pleiotropic functions such as lipid-lowering, anti-inflammatory, and scavenger receptors suppression 135. In a recent study, in patients with CHD (n=300) probucol treatment reduce atherosclerotic plaque area as well as total cholesterol and soluble thrombomodulin levels 88. Despite of these findings, prospective studies are needed to determine whether the combination therapy of probucol with lipid-lowering agents improves vascular outcomes in subjects with CHD. However, probucol reduces HDL-C caused by the activation of CETP 136 and hepatic scavenger receptor class B type I (SR-BI) 137. Given that, probucol was left by western countries, although it is still used for a long time, especially in Japan.
Novel therapeutic targets for reducing atherosclerotic plaque
New targets in atherosclerosis research have been reported. Some studies suggested that semaphorin-3A (sema-3A) reduces atherosclerotic plaque progression by enhancing the motility and function of M2 macrophages and regulating foam cell formation in apoE-/- mouse 138, 139. Conversely, sema-3E another semaphorin is expressed in atherosclerotic plaques and regulated macrophage retention in plaques 140. Further investigations are in need to evaluate semaphorin roles atherosclerotic plaque formation. Another target to promote regression of atherosclerosis is through activation of the chemokine receptor CCR7-dependent emigration pathway in macrophages 25, 105. In deed, targeting CCR7 activation by statins was found to induce CD68+ release from plaques rather promoting atherosclerotic plaque regression 141. This indicates a new prospect in reducing atherosclerotic plaques 142. However, the role of CCR7 in atherosclerosis is more complex. Furthermore, genomic studies revealed novel targets of proteins as a novel target for anti-atherosclerotic therapy 133. Theses are asialoglycoprotein receptor 1, angiopoietin-related protein 4, and inflammatory pathways that damage efferocytosis (CD47) (Table 2). There is a need to validate the impact such targets on plaque regression.
Angiogenesis inhibitors
Angiogenesis is associated closely with plaque progression 143, 144 where its role in this process may take part in plaque destabilization and thromboembolic acute events 143. Various compounds emerge as alternatives to promote plaque stability by targeting IP angiogenesis. Earlier studies have reported that anti-angiogenic compounds; endostatin and TNP-470 to reduce atherosclerosis progression in apoE-/-mice 145. Another agent is Ghrelin, a 28-amino-acid acylated peptide 146 was found to inhibit IP angiogenesis in animal models 147. As reported recently, ghrelin may act by regulating expression of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor 2 (VEGFR2) and reducing MCP-1 expression at late stage of atherosclerosis 143, 147. However, mechanism of action of Ghrelin on plaque stability have not yet been largely explored 147. Clinical trials with anti-angiogenic medications, mostly anti-VEGF/VEGFR, used in anticancer treatment, were associated with risk for cardiovascular adverse effects, and need further studies 144, 148. More recently, various compounds have been studied to inhibit IP angiogenesis with mechanism of action that interfere with angiogenesis 144, 147, 149 (Table 2). Studies based on a blocking antibody Bevacizumab against VEGF-A, Axitinib against VEGF receptor tyrosine kinase, and DC101 against VEGFR-2 showed potential ability for the treatment of IP angiogenesis and hemorrhage 149. Less studies targeting neovascularization were documented 108, possibly because of absence of relevant animal models. Previous works have showed that promotion of angiogenesis in myocardial ischemia is a potential strategy 2. However, angiogenesis promotes atherosclerosis growth in various animal models and probably causes plaque rupture 144, 148. Hence, more consideration should be paid to harmonize the regulation of angiogenesis in atherosclerotic CVD when using anti-angiogenic medications 148.
HDL biogenesis and plaque regression
Meta-analysis of clinical studies demonstrated that atherosclerosis regression as measured by (IVUS) after decreasing LDL levels was almost to be reached when HDL concentration was increased by 110. Despite this, sudden rupture of plaque remains the leading reason of acute coronary events 150-152. The role of HDL in plaque regression although still less well characterized 110. Infusion of reconstituted HDL into human subjects with acute coronary syndrome 116, 152 was found to promote regression of atherosclerosis lesion in 5 weeks of therapy 153. Other studies linked plaque regression to use of HDL mimetic peptides 116, 154 by targeting HDL biogenesis process through increasing apoA-I production or modulating ABCA1 155, 156. In vivo studies showed that macrophage cholesterol efflux (CE) mediated by ABCA1/ABCG1 may have an important role in suppressing apoptosis in advanced plaques 157. Defective HDL capacity in ABCA1 cholesterol efflux was observed in association with progressive atherosclerotic lesions 13. As established by us 71, 158, and others 159-161, an inverse association exists between HDL cholesterol efflux and carotid plaque instability and CVD, independently of the HDL-C levels. Although not yet determined, cholesterol efflux could be important biomarker in determining who will develop atherosclerosis. However, more recently, serum cholesterol efflux values do not correlate with plaque vulnerable markers in elderly subjects (~80 years, n=59) 162. One explanation is that cholesterol efflux may play a more protective role in the earlier steps of atherosclerosis 163. In support for this, cholesterol efflux association with cardiovascular events was found more evident in younger populations than others 162. More studies should be conducted to assess differences in HDL cholesterol according to atheromatous plaque severity or instability to better evaluate HDL biogenesis as therapeutic target for atherosclerosis (Table 2).
Locally applied therapy for vulnerable plaque
Other options exist for local therapy and plaque pacification. Photodynamic therapy broadly used in cancer patients, is explored in plaque regression therapies. This technology demonstrated ability to destroy mechanically macrophages and SMC without damaging structural integrity of the vessels with a photosensitizer 164. The application of photodynamic therapy is still limited 165 despite safety trails 164, 165. As recently reviewed, photodynamic therapy pertinence needs further evaluation and there is major challenges toward its translation into a clinical reality 166. Other options are with plaque sealing based on the concept that plaques may be intentionally ruptured with angioplasty balloon inflation after intervention 165. This technology is performed by placing a stent to prevent plaque acute events. However, this concept has fallen out of favor after the arrival of coronary stenting and the lack of clinical results 165. Nanoparticles approaches may provide possibilities of safe gene medication, with the goal of attenuating atherosclerosis 167 (Table 2). Of such, several important challenges persist regarding to nanoparticle drug delivery purposes where each particle arises from a unique set of design criteria and composite 168. Despite this, nanotechnology is exciting strategy for innovative effective medication as evidenced in vivo by reducing plaque at risk of rupture and changing in inflammatory markers. It would be important to know in a near future if these techniques would be associated with improvement in methods to detect “high-risk plaque” as well as improved stent technology and understanding of the so-called vulnerable plaques 62.
Conclusion
Our knowledge of plaque biology is increasingly expanding. The area of vulnerable plaque is receiving more awareness with the arrival of molecular imaging, letting better insight into plaque biology. Current advances in both atherosclerosis imaging and lipid-lowering treatment present additional questions for future consideration in the setting of reducing plaque at risk of rupture. Despite recent advances in primary prevention and therapeutic technology, treatment of atherosclerosis based on HDL biology remains in preclinical stages. Importantly, more effective effort should be directed toward developing more reliable models for an integrative approach to plaque assessment.
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