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Impact of lipid lowering on coronary atherosclerosis moving from the lumen to the artery wall

      Highlights

      • Intensive lipid lowering with statin monotherapy or combination therapy is achievable in most high risk patients.
      • Intensive lipid lowering slows progression of obstructive disease on coronary angiography.
      • Intensive lipid lowering promotes plaque regression and stabilization, proportional to LDL-C lowering.
      • These benefits are likely to underscore the impact of intensive lipid lowering on cardiovascular risk.

      Abstract

      Randomized clinical trials have demonstrated that increasingly intensive lowering of low-density lipoprotein cholesterol (LDL-C) reduces the rate of cardiovascular events in the primary and secondary prevention setting. Integration of serial coronary imaging within clinical trials has enabled evaluation of medical therapies on the natural history of coronary disease. These studies have extended from early investigation of coronary obstruction with angiography to more contemporary evaluation of plaque burden and composition with imaging modalities that directly visualize the artery wall. The findings of these trials have demonstrated that intensive lipid lowering promotes plaque regression and stabilization. The lessons of this body of research provide a biological rationale underscoring the ability of intensive lipid lowering to reduce cardiovascular risk and have the potential to promote greater uptake in clinical practice.

      Graphical abstract

      Keywords

      1. Introduction

      The role of low-density lipoprotein cholesterol (LDL-C) in the causality of atherosclerotic cardiovascular disease is well established [
      • Ference B.A.
      • Ginsberg H.N.
      • Graham I.
      • et al.
      Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel.
      ]. Population studies demonstrate a curvilinear relationship between LDL-C and cardiovascular risk and animal models have established that higher LDL-C levels associate with more extensive and vulnerable forms of atherosclerosis [
      • Ference B.A.
      • Ginsberg H.N.
      • Graham I.
      • et al.
      Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel.
      ]. Clinical trials support the benefits of lipid lowering, with the degree of benefit directly associated with the extent to which LDL-C levels are decreased [
      • Baigent C.
      • Blackwell L.
      • Emberson J.
      • et al.
      Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials.
      ]. These benefits are clear in both the primary and secondary prevention settings and evident with use of intensive statin therapy as monotherapy [
      • Baigent C.
      • Blackwell L.
      • Emberson J.
      • et al.
      Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials.
      ] and in combination with ezetimibe [
      • Cannon C.P.
      • Blazing M.A.
      • Giugliano R.P.
      • et al.
      Ezetimibe added to statin therapy after acute coronary syndromes.
      ] and proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors [
      • Sabatine M.S.
      • Giugliano R.P.
      • Keech A.C.
      • et al.
      Evolocumab and clinical outcomes in patients with cardiovascular disease.
      ,
      • Schwartz G.G.
      • Steg P.G.
      • Szarek M.
      • et al.
      Alirocumab and cardiovascular outcomes after acute coronary syndrome.
      ]. In parallel, clinical trials that have integrated serial coronary imaging have permitted the ability to elucidate the impact of lipid lowering interventions on atherosclerotic disease.

      2. Evolution of imaging of coronary atherosclerosis

      Since the late 1950's invasive coronary angiography has played an important role in the diagnosis and management of atherosclerotic coronary disease. Demonstrating the association between the extent of obstructive disease and adverse clinical outcomes [
      • Emond M.
      • Mock M.B.
      • Davis K.B.
      • et al.
      Long-term survival of medically treated patients in the coronary artery surgery study (CASS) registry.
      ] has enabled triage of patients to a range of revascularization strategies [
      • Chaitman B.R.
      • Fisher L.D.
      • Bourassa M.G.
      • et al.
      Effect of coronary bypass surgery on survival patterns in subsets of patients with left main coronary artery disease. Report of the Collaborative Study in Coronary Artery Surgery (CASS).
      ]. However, the finding that many patients with acute coronary syndromes don't have a tight stenosis and the natural history of remodeling of the artery wall with plaque development highlights the limitation of measures of lumen obstruction to fully visualize the full extent of atherosclerotic disease [
      • Falk E.
      • Shah P.K.
      • Fuster V.
      Coronary plaque disruption.
      ]. Accordingly, there has been considerable interest in the development of alternative coronary imaging approaches to provide more extensive characterization of atherosclerotic plaque.
      Intravascular ultrasound (IVUS) generates high resolution imaging of the full thickness of the artery wall enabling measurement of the extent of atherosclerotic disease [
      • Nicholls S.J.
      • Hsu A.
      • Wolski K.
      • et al.
      Intravascular ultrasound-derived measures of coronary atherosclerotic plaque burden and clinical outcome.
      ]. IVUS detects attenuated or low attenuated plaque regions, which have been demonstrated to associate with vulnerable disease, in addition to different patterns of plaque calcification, however, the ability to detect individual components of plaque is limited. Radiofrequency analysis of the IVUS backscatter generates a spectral tissue map with the IVUS virtual histology (IVUS-VH) technique validated to distinguish fibrotic, fibrofatty, necrotic and calcific components [
      • Stone G.W.
      • Maehara A.
      • Lansky A.J.
      • et al.
      A prospective natural-history study of coronary atherosclerosis.
      ]. Optical coherence tomography (OCT) employs light based imaging, with the ability to produce greater imaging resolution of the coronary artery wall. This greater resolution presents the ability to image superficial elements of plaque, such as fibrous cap thickness, accumulation of lipid and macrophages, in addition to detection of cholesterol crystals and neovascularization [
      • Araki M.
      • Park S.J.
      • Dauerman H.L.
      • et al.
      Optical coherence tomography in coronary atherosclerosis assessment and intervention.
      ]. While OCT has limited penetration of the full thickness of the artery wall and fails to reliably measure plaque burden, it has the potential to detect features consistent with plaque vulnerability [
      • Araki M.
      • Park S.J.
      • Dauerman H.L.
      • et al.
      Optical coherence tomography in coronary atherosclerosis assessment and intervention.
      ]. More recent application of near infrared spectroscopy (NIRS) has the potential to characterize the chemical composition of atherosclerosis, with early applications focused on generating a semiquantitative measurement of plaque lipid content [
      • Waksman R.
      • Di Mario C.
      • Torguson R.
      • et al.
      Identification of patients and plaques vulnerable to future coronary events with near-infrared spectroscopy intravascular ultrasound imaging: a prospective, cohort study.
      ]. The ability to use these techniques in clinical research, with serial imaging of a matched arterial segment, provide the opportunity to study the impact of clinical factors and medical therapies.
      These techniques provide additional approaches to imaging coronary atherosclerosis. Invasive pressure wires enable assessment of the physiological consequences of arterial stenoses and are increasingly used in the clinical assessment of patients in the catheterization laboratory [
      • Barbato E.
      • Toth G.G.
      • Johnson N.P.
      • et al.
      A prospective natural history study of coronary atherosclerosis using fractional flow reserve.
      ]. Development of a range of molecular imaging approaches provides the opportunity to detect additional components of plaque [
      • Dweck M.R.
      • Aikawa E.
      • Newby D.E.
      • et al.
      Noninvasive molecular imaging of disease activity in atherosclerosis.
      ]. Increasing use of non-invasive coronary imaging, primarily with computed tomography (CT), enables to study patients across a broader spectrum of clinical risk [
      • Figtree G.A.
      • Adamson P.D.
      • Antoniades C.
      • et al.
      Noninvasive plaque imaging to accelerate coronary artery disease drug development.
      ]. In parallel, there remain efforts to improve the ability of magnetic resonance imaging (MRI) to visualize coronary arteries, given its demonstrated utility to accurately image plaque within larger arteries [
      • Wust R.C.I.
      • Calcagno C.
      • Daal M.R.R.
      • et al.
      Emerging magnetic resonance imaging techniques for atherosclerosis imaging.
      ] (Fig. 1).
      Fig. 1
      Fig. 1Coronary imaging modalities.
      Imaging of coronary atherosclerosis by coronary angiography (left), optical coherence tomography (upper middle), intravascular ultrasound (upper right), intravascular ultrasound virtual histology (lower middle) and near infrared spectroscopy (lower right).

      3. Lipid lowering and coronary obstructive disease

      Early validation of quantitative coronary angiography enabled integration of lipid lowering therapies within clinical trials. These studies evaluated statins and demonstrated a direct association between degree of LDL-C lowering and slowing the rate of progression of obstructive disease [
      • Ballantyne C.M.
      Clinical trial endpoints: angiograms, events, and plaque instability.
      ,
      • Ballantyne C.M.
      • Raichlen J.S.
      • Nicholls S.J.
      • et al.
      Effect of rosuvastatin therapy on coronary artery stenoses assessed by quantitative coronary angiography: a study to evaluate the effect of rosuvastatin on intravascular ultrasound-derived coronary atheroma burden.
      ]. While studies of LDL apheresis in patients with familial hypercholesterolaemia have been reported to produce angiographic regression, this has been more challenging to demonstrate with pharmacological agents [
      • Kroon A.A.
      • Aengevaeren W.R.
      • van der Werf T.
      • et al.
      LDL-Apheresis Atherosclerosis Regression Study (LAARS). Effect of aggressive versus conventional lipid lowering treatment on coronary atherosclerosis.
      ]. Where regression has been demonstrated, it has been in segments with either baseline stenoses greater than 25% or where there was marked regression of the burden of atherosclerotic plaque [
      • Ballantyne C.M.
      • Raichlen J.S.
      • Nicholls S.J.
      • et al.
      Effect of rosuvastatin therapy on coronary artery stenoses assessed by quantitative coronary angiography. A study to evaluate the effect of rosuvastatin on intravascular ultrasound-derived coronary atheroma burden.
      ]. Given the established association between obstructive disease on angiography and adverse cardiovascular outcomes [
      • Emond M.
      • Mock M.B.
      • Davis K.B.
      • et al.
      Long-term survival of medically treated patients in the coronary artery surgery study (CASS) registry.
      ], the results from quantitative angiography studies have played an important role in the regulatory approval and labelling process for anti-atherosclerotic agents.

      4. Lipid lowering and coronary plaque burden

      IVUS was primarily developed to assist the interventional cardiologist to more effectively manage coronary obstructive disease, however, its ability to precisely measure the full burden of atherosclerotic plaque within an arterial segment underscored its use in clinical trials to evaluate the effect of medical therapies. These studies have provided important insights into the effect of increasingly intensive lowering of LDL-C. Early clinical trials of statin therapy demonstrated the ability to slow progression of coronary atherosclerosis [
      • Nissen S.E.
      • Tuzcu E.M.
      • Schoenhagen P.
      • et al.
      Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial.
      ]. A number of key studies have demonstrated the impact of increasingly intensive lipid lowering on coronary plaque burden (Fig. 2).
      Fig. 2
      Fig. 2Change in percent atheroma volume and lipid lowering.
      Change in percent atheroma volume (PAV) in intravascular ultrasound clinical trials using intravascular ultrasound of statin therapy (upper panel) and use of additional lipid lowering agents in combination with statins (lower panel). ALI, alirocumab; ATV, atorvastatin; EZE, ezetimibe; EVO, evolocumab; PRA, pravastatin; RSV, rosuvastatin.
      The Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) study compared the effects of a moderate (pravastatin 40 mg) and intensive (atorvastatin 80 mg) statin strategy for 18 months on IVUS disease progression [
      • Nissen S.E.
      • Tuzcu E.M.
      • Schoenhagen P.
      • et al.
      Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial.
      ]. Lower LDL-C levels with atorvastatin (79 vs 110 mg/dL) associated with imaging benefits, with evidence of plaque progression with pravastatin, but not atorvastatin. This study demonstrated the ability to arrest disease progression with more intensive lipid lowering. A linear association was observed between changes in plaque burden and both the degree of lowering levels of LDL-C and high sensitivity C-reactive protein (hsCRP) [
      • Nissen S.E.
      • Tuzcu E.M.
      • Schoenhagen P.
      • et al.
      Statin therapy, LDL cholesterol, C-reactive protein, and coronary artery disease.
      ]. The hsCRP effect was independent of the impact of lipid lowering and suggested that anti-inflammatory properties of statins may contribute to their benefit on coronary atherosclerosis.
      A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden (ASTEROID) was an open label investigation of the impact of high dose rosuvastatin therapy for 24 months with no comparator arm [
      • Nissen S.E.
      • Nicholls S.J.
      • Sipahi I.
      • et al.
      Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial.
      ]. This study of 349 patients demonstrated a significant reduction in all measures of plaque burden at follow up compared to baseline in patients achieving a lower LDL-C level (60 mg/dL). ASTEROID was the first large study to demonstrate that the ability to achieve lipid targets with high intensity statin therapy could promote plaque regression (percent atheroma volume reduction 0.98%). Subsequent analyses demonstrated that both intensive lowering of LDL-C and modest raising of high-density lipoprotein cholesterol (HDL-C) independently associated with the ability of statins to attenuate plaque progression [
      • Nicholls S.J.
      • Tuzcu E.M.
      • Sipahi I.
      • et al.
      Statins, high-density lipoprotein cholesterol, and regression of coronary atherosclerosis.
      ].
      The Study of Coronary Atheroma by Intravascular Ultrasound: Effect of Rosuvastatin versus Atorvastatin (SATURN) extended on these observations to directly compare the effects of the highest doses of atorvastatin and rosuvastatin for 24 months [
      • Nicholls S.J.
      • Ballantyne C.M.
      • Barter P.J.
      • et al.
      Effect of two intensive statin regimens on progression of coronary disease.
      ]. Achieving low levels of LDL-C in both the atorvastatin (70 mg/dL) and rosuvastatin (62 mg/dL) groups was associated with significant reductions in plaque burden during the study (0.99% and 1.22% reductions in percent atheroma volume, respectively). The findings of SATURN firmly established that use of high intensity statins could lower LDL-C levels to the range recommended by treatment guidelines and that this would promote disease regression in the majority of patients. This was supported by observations of a continuous relationship between achieved LDL-C levels and changes in plaque burden down to 60 mg/dL, with evidence that regression starts to appear at levels beyond 70 mg/dL [
      • Nicholls S.J.
      • Ballantyne C.M.
      • Barter P.J.
      • et al.
      Effect of two intensive statin regimens on progression of coronary disease.
      ].
      The Japan Assessment of Pitavastatin and Atorvastatin in Acute Coronary Syndrome (JAPAN-ACS) study evaluated the impact of treatment with either pitavastatin 4 mg or atorvastatin 20 mg for 8–12 months in patients following an acute ischaemic event [
      • Hiro T.
      • Kimura T.
      • Morimoto T.
      • et al.
      Effect of intensive statin therapy on regression of coronary atherosclerosis in patients with acute coronary syndrome: a multicenter randomized trial evaluated by volumetric intravascular ultrasound using pitavastatin versus atorvastatin (Japan-ACS [Japan assessment of pitavastatin and atorvastatin in acute coronary syndrome] study).
      ]. This study demonstrated a similar degree of regression by approximately 17% in both groups, suggesting that substantial reductions in plaque might be achievable in patients with more biologically active disease. This is supported by the findings of a small, single centre study in which regression was observed with 12 months of treatment with atorvastatin 20 mg (13% reduction in plaque burden) compared with placebo (9% increase in plaque burden) [
      • Okazaki S.
      • Yokoyama T.
      • Miyauchi K.
      • et al.
      Early statin treatment in patients with acute coronary syndrome: demonstration of the beneficial effect on atherosclerotic lesions by serial volumetric intravascular ultrasound analysis during half a year after coronary event: the ESTABLISH Study.
      ], and a post hoc analysis of SATURN, in which a greater absolute regression of percent atheroma volume (−1.46 vs −0.89%) was observed in high intensity statin treated patients with an acute coronary syndrome compared with more stable disease [
      • Puri R.
      • Nissen S.E.
      • Shao M.
      • et al.
      Antiatherosclerotic effects of long-term maximally intensive statin therapy after acute coronary syndrome: insights from Study of Coronary Atheroma by Intravascular Ultrasound: effect of Rosuvastatin versus Atorvastatin.
      ]. The finding of potentially greater impact of statin therapy in patients with an acute coronary syndrome may reflect the greater plaque burden at baseline compared with stable patients, the biological activity within the plaque and the combined effects of statin therapy on LDL-C and hsCRP.
      Subsequent analyses of the statin trials demonstrated that approximately one third of patients treated with high intensity statin therapy demonstrate ongoing plaque progression. These patients typically harboured a greater number of suboptimally controlled risk factors and higher levels of apolipoprotein B (apoB) [
      • Bayturan O.
      • Kapadia S.
      • Nicholls S.J.
      • et al.
      Clinical predictors of plaque progression despite very low levels of low-density lipoprotein cholesterol.
      ]. The later observation suggested that achieving guideline recommended LDL-C levels may not reflect sufficiently optimal lipid lowering if the circulating burden of atherogenic lipoproteins, reflected by apoB levels, remains high. Accordingly, there may be additional benefit that can be derived from the use of combination lipid lowering strategies as opposed to statin monotherapy. The Plaque Regression with Cholesterol Absorption Inhibitor or Synthesis Inhibitor Evaluated by Intravascular Ultrasound (PRECISE-IVUS) compared the effects of atorvastatin monotherapy uptitrated to achieve an LDL-C level below 70 mg/dL and in combination with ezetimibe for 9–12 months [
      • Tsujita K.
      • Sugiyama S.
      • Sumida H.
      • et al.
      Impact of dual lipid-lowering strategy with ezetimibe and atorvastatin on coronary plaque regression in patients with percutaneous coronary intervention: the multicenter randomized controlled PRECISE-IVUS trial.
      ]. The combination of atorvastatin and ezetimibe produced lower LDL-C levels (63 vs 73 mg/dL) and greater plaque regression (reduction in percent atheroma volume 1.4 vs 0.3%). This finding complemented the findings that the combination of statin and ezetimibe had a favourable effect on cardiovascular events compared with statin monotherapy in patients following an acute coronary syndrome [
      • Cannon C.P.
      • Blazing M.A.
      • Giugliano R.P.
      • et al.
      Ezetimibe added to statin therapy after acute coronary syndromes.
      ].
      The development of PCSK9 inhibitors presented the opportunity to achieve substantially lower LDL-C levels for the majority of high cardiovascular risk patients. This enables most patients to achieve treatment targets and very low LDL-C levels. The Global Assessment of Plaque Regression with a PCSK9 Antibody as Measured by Intravascular Ultrasound (GLAGOV) compared the effects of treatment with evolocumab and placebo for 18 months in patients who had been treated with a statin for at least four weeks [
      • Nicholls S.J.
      • Puri R.
      • Anderson T.
      • et al.
      Effect of evolocumab on progression of coronary disease in statin-treated patients: the GLAGOV randomized clinical trial.
      ]. Achieving a lower LDL-C level with the addition of evolocumab (37 vs 93 mg/dL) was associated with plaque regression (reduction in percent atheroma volume 0.95% compared with increase by 0.05% in the placebo group), with evidence of a direct relationship between achieved LDL-C and changes in percent atheroma volume extended down to 20 mg/dL. More recent IVUS analyses of clinical trials of PCSK9 inhibitors conducted in patients with acute coronary syndromes demonstrated greater regression than observed in the stable patients in GLAGOV (greater than 2% reduction in percent atheroma volume) [
      • Raber L.
      • Ueki Y.
      • Otsuka T.
      • et al.
      Effect of alirocumab added to high-intensity statin therapy on coronary atherosclerosis in patients with acute myocardial infarction: the PACMAN-AMI randomized clinical trial.
      ,
      • Nicholls S.J.
      • Kataoka Y.
      • Nissen S.E.
      • et al.
      Effect of evolocumab on coronary plaque phenotype and burden in statin-treated patients following myocardial infarction.
      ]. While these studies demonstrated greater plaque burden at baseline in acute coronary syndrome patients, the findings may also suggest the presence of a more biologically active form of disease that may be more modifiable with intensive lipid lowering. These findings support the results of clinical trials that demonstrated that addition of a PCSK9 inhibitor to statin therapy reduces cardiovascular risk in patients with both stable and recently unstable forms of disease [
      • Sabatine M.S.
      • Giugliano R.P.
      • Keech A.C.
      • et al.
      Evolocumab and clinical outcomes in patients with cardiovascular disease.
      ,
      • Schwartz G.G.
      • Steg P.G.
      • Szarek M.
      • et al.
      Alirocumab and cardiovascular outcomes after acute coronary syndrome.
      ].

      5. Lipid lowering and coronary plaque composition

      Increasing attention has focussed on the role of plaque composition in driving cardiovascular risk. Pathology studies have established that vulnerable plaque features including the presence of lipid and inflammatory material, in addition to a thin fibrous cap, neovascularization, cholesterol crystals and outward remodeling of the artery wall, are more typically encountered in patients with acute coronary syndromes [
      • Falk E.
      • Shah P.K.
      • Fuster V.
      Coronary plaque disruption.
      ]. A range of imaging modalities have the ability to visualize these features in vivo. The presence of high risk features (high plaque burden, spotty calcification, outward artery wall remodeling) identifies patients with more progressive forms of disease on IVUS and greater regression with statin therapy [
      • Kataoka Y.
      • Wolski K.
      • Balog C.
      • et al.
      Progression of coronary atherosclerosis in stable patients with ultrasonic features of high-risk plaques.
      ]. Beyond the ability of imaging to identify a more modifiable form of disease, the integration of these modalities in clinical trials has also permitted the impact of lipid lowering interventions on plaque composition.
      Conventional IVUS imaging provides a limited characterization of plaque components. These trials have demonstrated that use of high dose statin therapy [
      • Puri R.
      • Nicholls S.J.
      • Shao M.
      • et al.
      Impact of statins on serial coronary calcification during atheroma progression and regression.
      ,
      • Puri R.
      • Libby P.
      • Nissen S.E.
      • et al.
      Long-term effects of maximally intensive statin therapy on changes in coronary atheroma composition: insights from SATURN.
      ] and the combination of statins and evolocumab [
      • Nicholls S.J.
      • Puri R.
      • Anderson T.
      • et al.
      Effect of evolocumab on coronary plaque composition.
      ] result in an increase in plaque calcification on IVUS imaging. These findings are supported by IVUS-VH analysis of the SATURN and GLAGOV trials and meta-analysis of 9 trials of statin therapy demonstrating that intensive lipid lowering therapies produced increases in plaque calcification, with this relationship directly proportional to achieved LDL-C levels [
      • Banach M.
      • Serban C.
      • Sahebkar A.
      • et al.
      Impact of statin therapy on coronary plaque composition: a systematic review and meta-analysis of virtual histology intravascular ultrasound studies.
      ]. Increases in plaque calcification accompanying regression with intensive lipid lowering contribute to plaque stabilization. This is supported by observations from serial computed tomography coronary angiography (CTCA) which demonstrate that the pattern of calcium that develops with statin therapy is high density [
      • van Rosendael A.R.
      • Narula J.
      • Lin F.Y.
      • et al.
      Association of high-density calcified 1K plaque with risk of acute coronary syndrome.
      ]. It also has implications for the use of serial calcium scoring in patients treated with lipid lowering agents, which will confound interpretation of the findings. While IVUS-VH imaging identifies necrotic material within plaque, no intravascular imaging trial has demonstrated reductions in necrotic material with lipid lowering therapies [
      • Puri R.
      • Libby P.
      • Nissen S.E.
      • et al.
      Long-term effects of maximally intensive statin therapy on changes in coronary atheroma composition: insights from SATURN.
      ,
      • Nicholls S.J.
      • Puri R.
      • Anderson T.
      • et al.
      Effect of evolocumab on coronary plaque composition.
      ,
      • Oemrawsingh R.M.
      • Garcia-Garcia H.M.
      • van Geuns R.J.
      • et al.
      Integrated Biomarker and Imaging Study 3 (IBIS-3) to assess the ability of rosuvastatin to decrease necrotic core in coronary arteries.
      ,
      • Raber L.
      • Taniwaki M.
      • Zaugg S.
      • et al.
      Effect of high-intensity statin therapy on atherosclerosis in non-infarct-related coronary arteries (IBIS-4): a serial intravascular ultrasonography study.
      ]. The finding that high dose rosuvastatin did reduce the size of the lipid rich necrotic core on magnetic resonance imaging of carotid plaque [
      • Underhill H.R.
      • Yuan C.
      • Zhao X.Q.
      • et al.
      Effect of rosuvastatin therapy on carotid plaque morphology and composition in moderately hypercholesterolemic patients: a high-resolution magnetic resonance imaging trial.
      ] is of interest, but the variable results with different imaging tools suggest that serial monitoring of coronary necrotic material is not a useful tool to evaluate medical therapies.
      The ability to more directly visualize vulnerable plaque components with OCT imaging provides a more effective tool for the investigation of lipid lowering. Observational studies have demonstrated that higher LDL-C levels and the presence of cholesterol crystals associate with more vulnerable plaque features on OCT [
      • Kataoka Y.
      • Hammadah M.
      • Puri R.
      • et al.
      Plaque microstructures in patients with coronary artery disease who achieved very low low-density lipoprotein cholesterol levels.
      ]. Additional investigations demonstrated more stable plaque in patients treated with higher doses of statins [
      • Kataoka Y.
      • Puri R.
      • Hammadah M.
      • et al.
      Frequency-domain optical coherence tomographic analysis of plaque microstructures at nonculprit narrowings in patients receiving potent statin therapy.
      ]. Serial OCT imaging has been integrated in several clinical trials of statin therapy [
      • Kataoka Y.
      • Puri R.
      • Hammadah M.
      • et al.
      Frequency-domain optical coherence tomographic analysis of plaque microstructures at nonculprit narrowings in patients receiving potent statin therapy.
      ,
      • Dai J.
      • Hou J.
      • Xing L.
      • et al.
      Is age an important factor for vascular response to statin therapy? A serial optical coherence tomography and intravascular ultrasound study.
      ,
      • Hattori K.
      • Ozaki Y.
      • Ismail T.F.
      • et al.
      Impact of statin therapy on plaque characteristics as assessed by serial OCT, grayscale and integrated backscatter-IVUS.
      ,
      • Hou J.
      • Xing L.
      • Jia H.
      • et al.
      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.
      ,
      • Komukai K.
      • Kubo T.
      • Kitabata H.
      • et al.
      Effect of atorvastatin therapy on fibrous cap thickness in coronary atherosclerotic plaque as assessed by optical coherence tomography: the EASY-FIT study.
      ,
      • Nishio R.
      • Shinke T.
      • Otake H.
      • et al.
      Stabilizing effect of combined eicosapentaenoic acid and statin therapy on coronary thin-cap fibroatheroma.
      ,
      • Takarada S.
      • Imanishi T.
      • Kubo T.
      • et al.
      Effect of statin therapy on coronary fibrous-cap thickness in patients with acute coronary syndrome: assessment by optical coherence tomography study.
      ]. The largest of these studies, the Effect of Atorvastatin Therapy on Fibrous Cap Thickness in Coronary Atherosclerotic Plaque as Assessed by Optical Coherence Tomography (EASY-FIT) trial compared the effects of treatment with atorvastatin 5 and 20 mg for 12 months [
      • Komukai K.
      • Kubo T.
      • Kitabata H.
      • et al.
      Effect of atorvastatin therapy on fibrous cap thickness in coronary atherosclerotic plaque as assessed by optical coherence tomography: the EASY-FIT study.
      ]. The higher dose group achieved a lower LDL-C (69 vs 78 mg/dL), which associated with larger absolute increases in fibrous cap thickness and decreases in lipid arc. In a similar fashion as the IVUS studies, increasing fibrous cap thickness also independently associated with hsCRP lowering, supporting the concept that statins possess anti-inflammatory properties. Meta-regression analysis of these statin trials demonstrated a linear association between lowering of LDL-C and increases in fibrous cap thickness [
      • Nicholls S.J.
      • Nissen S.E.
      • Prati F.
      • et al.
      Assessing the impact of PCSK9 inhibition on coronary plaque phenotype with optical coherence tomography: rationale and design of the randomized, placebo-controlled HUYGENS study.
      ].
      A small study comparing the effects of treatment with ezetimibe or placebo in addition to background fluvastatin for 9 months demonstrated that lower LDL-C levels in the combination group (89 vs 101 mg/dL) associated with plaque stabilization. The combination of ezetimibe and fluvastatin achieved greater increases in fibrous cap thickness (80 vs 40 μm) and a similar reduction in the lipid arc angle in both groups [
      • Habara M.
      • Nasu K.
      • Terashima M.
      • et al.
      Impact on optical coherence tomographic coronary findings of fluvastatin alone versus fluvastatin + ezetimibe.
      ].
      The High-Resolution Assessment of Coronary Plaques in a Global Evolocumab Randomized Study (HUYGENS) compared the effects of treatment with the PCSK9 inhibitor evolocumab and placebo for 12 months on plaque composition features on serial OCT imaging in patients following an acute coronary syndrome [
      • Nicholls S.J.
      • Kataoka Y.
      • Nissen S.E.
      • et al.
      Effect of evolocumab on coronary plaque phenotype and burden in statin-treated patients following myocardial infarction.
      ]. Only 25% of patients had been treated with a statin prior to their acute coronary syndrome, the expectation was that all patients would be treated in accordance with treatment guidelines during the study. This resulted in more than 95% of patients treated with a statin, of which more than 80% was high intensity in nature. At 12 months, the patients treated with the combination of statin and evolocumab demonstrated lower LDL-C levels (28 vs 87 mg/dL), with more than 90% achieving the target of less than 70 mg/dL. The statin/evolocumab group demonstrated greater increases in minimum fibrous cap thickness (+42.7 vs + 21.5 μm) and decreases in maximum lipid arc (−57.5 vs −31.4°) and macrophage index (−3.35 vs −1.43). Similar benefits of treatment with statin and evolocumab were observed in lipid rich plaque regions. A direct relationship was observed between thickening of the fibrous cap and degree of intensity of lipid lowering.
      The Effects of the PCSK9 Antibody Alirocumab on Coronary Atherosclerosis in Patients with Acute Myocardial Infarction (PACMAN-AMI) study investigated the impact of alirocumab compared with placebo for 12 months in patients following a myocardial infarction treated with rosuvastatin 20 mg [
      • Raber L.
      • Ueki Y.
      • Otsuka T.
      • et al.
      Effect of alirocumab added to high-intensity statin therapy on coronary atherosclerosis in patients with acute myocardial infarction: the PACMAN-AMI randomized clinical trial.
      ]. In this study, treatment with alirocumab and rosuvastatin produced lower LDL-C levels (24 vs 74 mg/dL), which associated with a greater increase in fibrous cap thickness (+62.7 vs + 33.2 μm) and decrease in macrophage arc (−26 vs −16°). The complementary findings of HUYGENS and PACMAN-AMI are important (Fig. 3, Fig. 4). They suggest that addition of a PCSK9 inhibitor to intensive statin therapy in patients following an acute coronary syndrome can produce effective lipid lowering, marked plaque regression and features consistent with plaque stabilization at 12 month follow up. A small, observational study provides some insight into the potential early development of these imaging benefits, with evidence of greater increases in fibrous cap thickness and decreases in the size of the lipid arc at 4 week follow up [
      • Yano H.
      • Horinaka S.
      • Ishimitsu T.
      Effect of evolocumab therapy on coronary fibrous cap thickness assessed by optical coherence tomography in patients with acute coronary syndrome.
      ].
      Fig. 3
      Fig. 3Change in minimum fibrous cap thickness with intensive lipid lowering following acute coronary syndromes.
      Change in fibrous cap thickness in statin treated patients with and without PCSK9 inhibitors on serial OCT imaging following an acute coronary syndrome. OCT, optical coherence tomography; PCSK9, proprotein convertase subtilisin kexin type 9.
      Fig. 4
      Fig. 4Change in lipid and macrophages with intensive lipid lowering following acute coronary syndromes.
      Change in plaque lipid (upper panels) and macrophage (lower panels) content in statin treated patients with and without PCSK9 inhibitors following an acute coronary syndrome. PCSK9, proprotein convertase subtilisin kexin type 9.
      Serial NIRS imaging has been less frequently employed in clinical trials. The Reduction in Yellow Plaque by Aggressive Lipid Lowering Therapy (YELLOW) study was conducted at a single centre and compared the effects of standard lipid lowering and more intensive therapy with rosuvastatin 40 mg for 7 weeks [
      • Kini A.S.
      • Baber U.
      • Kovacic J.C.
      • et al.
      Changes in plaque lipid content after short-term intensive versus standard statin therapy: the YELLOW trial (reduction in yellow plaque by aggressive lipid-lowering therapy).
      ]. Greater absolute reductions in the lipid core burden index were observed in the more intensive treatment group (−149.1 vs + 2.4), although this group also demonstrated higher baseline levels. While the Integrated Biomarker and Imaging Studies (IBIS-3) of rosuvastatin 40 mg failed to demonstrate any change in lipid core burden index, a trend toward benefit was observed in patients with higher baseline levels [
      • Oemrawsingh R.M.
      • Garcia-Garcia H.M.
      • van Geuns R.J.
      • et al.
      Integrated Biomarker and Imaging Study 3 (IBIS-3) to assess the ability of rosuvastatin to decrease necrotic core in coronary arteries.
      ]. The PACMAN-AMI also employed serial NIRS imaging, with evidence of a greater reduction in lipid core burden index in patients treated with alirocumab and statin (−79.4 vs −37.6) compared with statin monotherapy [
      • Raber L.
      • Ueki Y.
      • Otsuka T.
      • et al.
      Effect of alirocumab added to high-intensity statin therapy on coronary atherosclerosis in patients with acute myocardial infarction: the PACMAN-AMI randomized clinical trial.
      ]. The impact of evolocumab on serial NIRS imaging is currently being evaluated in an ongoing clinical trial []. The emerging data in the NIRS field suggests that more intensive lipid lowering does have a favourable impact on plaque lipid.

      6. Linking the imaging benefits to cardiovascular risk

      The rationale for conducting clinical trials with serial plaque imaging relates to the fundamental role that atherosclerosis plays in cardiovascular disease. This is supported by longstanding evidence of a relationship between the extent of atherosclerotic disease and the risk of clinical events. The findings with coronary angiography has led to its acceptance as a valid surrogate endpoint by regulatory authorities. The challenge for all subsequent modalities has been to meet that level of acceptance. While the changes observed in the serial IVUS trials are modest, a number of lines of evidence suggest that they are clinically relevant. Measures of plaque burden and progression have been demonstrated to associate with the risk of cardiovascular events [
      • Nicholls S.J.
      • Hsu A.
      • Wolski K.
      • et al.
      Intravascular ultrasound-derived measures of coronary atherosclerotic plaque burden and clinical outcome.
      ]. The difference in change in percent atheroma volume between patients who experience a clinical event and those who do not is approximately 0.55% [
      • Nicholls S.J.
      • Hsu A.
      • Wolski K.
      • et al.
      Intravascular ultrasound-derived measures of coronary atherosclerotic plaque burden and clinical outcome.
      ], with a meta-analysis of IVUS trials demonstrating that each nominal 1% reduction in percent atheroma volume associates with a 21% decrease in the risk of major adverse cardiovascular events [
      • Bhindi R.
      • Guan M.
      • Zhao Y.
      • et al.
      Coronary atheroma regression and adverse cardiac events: a systematic review and meta-regression analysis.
      ]. Observations from clinical trials in patients with acute coronary syndromes demonstrated a greater freedom from future clinical events in those who demonstrate plaque regression [
      • Dohi T.
      • Miyauchi K.
      • Okazaki S.
      • et al.
      Plaque regression determined by intravascular ultrasound predicts long-term outcomes of patients with acute coronary syndrome.
      ]. In a similar fashion, evidence of plaque vulnerable features on IVUS-VH, OCT and NIRS imaging associate with the risk of clinical events. The presence of a thin cap fibroatheroma on IVUS-VH independently associates with a greater risk of cardiovascular events, which is additive to markers of more extensive plaque burden [
      • Stone G.W.
      • Maehara A.
      • Lansky A.J.
      • et al.
      A prospective natural-history study of coronary atherosclerosis.
      ]. From an OCT perspective, the presence of lipid rich plaque associates with prospective cardiovascular risk, which appears to directly relate to the number of vulnerable plaque features [
      • Xing L.
      • Higuma T.
      • Wang Z.
      • et al.
      Clinical significance of lipid-rich plaque detected by optical coherence tomography: a 4-year follow-up study.
      ,
      • Prati F.
      • Romagnoli E.
      • Gatto L.
      • et al.
      Relationship between coronary plaque morphology of the left anterior descending artery and 12 months clinical outcome: the CLIMA study.
      ]. The presence of more extensive plaque lipid on NIRS imaging has been demonstrated to independently associate with a greater risk of major adverse cardiovascular events [
      • Waksman R.
      • Di Mario C.
      • Torguson R.
      • et al.
      Identification of patients and plaques vulnerable to future coronary events with near-infrared spectroscopy intravascular ultrasound imaging: a prospective, cohort study.
      ]. Ongoing efforts will be required to understand the true relationship between serial changes in these parameters and cardiovascular events. Ultimately, the finding that intensive statin therapy and the combination of statins with either ezetimibe or PCSK9 inhibitors result in less cardiovascular events in large clinical trials is an important validation of the relevance of the imaging findings. They provide a biological rationale underscoring the reduction in events and have the potential to promote patient adherence with long term achievement of intensive lipid lowering (Fig. 5).
      Fig. 5
      Fig. 5Impact of intensive lipid lowering on plaque.
      Impact of intensive lipid lowering on vulnerable plaque involves reduction in plaque size and reduction of vulnerable plaque features, including a reduction of lipid and inflammatory material in combination with an increase in fibrous cap thickness.

      7. Future directions

      As recent technological advances in arterial wall imaging have enabled new insights into the effects of intensive lipid lowering on coronary atherosclerosis, ongoing efforts will attempt to provide a greater understanding of these biological effects. Molecular imaging enables the ability to visualize specific elements within the atherosclerotic plaque that confer vulnerability and their integration into clinical trials has the potential to deliver additional insights. Non-invasive imaging with CTCA provides the opportunity to deliver a comprehensive assessment of atherosclerotic plaque (burden, composition, fractional flow reserve, perivascular adipose inflammation) and to do so in a broader range of patients than intravascular imaging studies. It is likely that CTCA will be increasingly integrated in clinical trials of medical therapies. The ability to overcome resolution challenges of coronary imaging with magnetic resonance might also permit combining vascular assessment with myocardial structure and function.

      8. Summary

      Advances in arterial wall imaging have extended our ability to characterize atherosclerotic disease from its luminal stenosis through to burden and composition. When integrated within clinical trials of lipid lowering therapies, these modalities have advanced our understanding of the impact of achieving increasingly low LDL-C levels. These studies have established that most patients with atherosclerotic coronary disease can achieve guideline mandated LDL-C targets and that this associates with both plaque regression and stabilization. This has important implications for understanding how intensive lipid lowering reduces cardiovascular risk.

      Declaration of competing interest

      The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Y.K. has received research support from Kowa, and speaker honoraria from Abbott Vascular, Amgen, CSL Behring, Daiichi Sankyo, Kowa, Nipro, and Takeda. S.J.N. has received research support from AstraZeneca, Amgen, Anthera, CSL Behring, Cerenis, Eli Lilly, Esperion, Resverlogix, Novartis, InfraReDx and Sanofi-Regeneron and is a consultant for Amgen, Akcea, AstraZeneca, Boehringer Ingelheim, CSL Behring, Eli Lilly, Esperion, Kowa, Merck, Takeda, Pfizer, Sanofi-Regeneron and Novo Nordisk. All other authors have no relationships to disclose.

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