Kiyoko Uno

Biomarkers of inflammation and oxidative stress in atherosclerosis

Increasing evidence has highlighted the roles of oxidative stress and inflammation in the promotion of atherosclerotic cardiovascular disease. Recent pathological studies have elucidated specific mediators that appear to link these pathways to the progression and rupture of atherosclerotic plaque in the artery wall. The ability to measure levels of these mediators in the systemic circulation has provoked interest in their development as biomarkers for potential use in risk assessment and in evaluation of the response to the use of preventive therapies. The discovery of these pathological mediators and their potential translation to the clinical arena will be reviewed.

Atheroma Progression in Hyporesponders to Statin Therapy

Objective— Lowering low-density lipoprotein cholesterol (LDL-C) with statins has been demonstrated to slow plaque progression. This antiatherosclerotic effect in patients with minimal LDL-C lowering has not been investigated. Approach and Results— Six hundred forty-seven patients with angiographic coronary artery disease who were commenced on statin therapy underwent serial imaging with intravascular ultrasound. Responders were defined as a percentage reduction in LDL-C of <15%. Disease progression was compared in responders (n=517) and hyporesponders (n=130) to statin therapy. Twenty percentage of patients demonstrated minimal changes in LDL-C, despite commencement of statin therapy. Statin hyporesponders were younger (55 versus 57 years; P=0.01), more likely to be male (79% versus 66%; P=0.005), and obese (body mass index, 31.5±6.1 versus 30.3±5.9 kg/m2; P=0.04) and less likely to have a history of dyslipidemia (50% versus 66%; P<0.001). Baseline levels of systolic blood pressure (127±15 versus 132±17 mm Hg; P=0.01) and LDL-C (2.5±0.6 versus 3.4±0.8 mmol/L; P<0.001) were lower in statin hyporesponders. Baseline percent atheroma volume was similar between statin hyporesponders and responders (36.9±9.8% versus 38.3±9.2%; P=0.13). On serial evaluation, greater progression of percent atheroma volume (1.19±0.48% versus 0.09±0.43%; P=0.003) was observed in statin hyporesponders. After adjusting for baseline clinical characteristics and measures of plaque burden, statin hyporesponders still exhibited greater atheroma progression (+0.83±0.58% versus −0.21±0.52%; P=0.006). Conclusions— A substantial proportion of patients with coronary artery disease fail to achieve effective reductions in LDL-C, despite prescription of statin therapy. Greater progression of atherosclerosis is observed in these patients. Our current study underscores monitoring LDL-C level after the commencement of statin to ensure adequate response to statin therapy.

Spotty calcification and plaque vulnerability in vivo : frequency-domain optical coherence tomography analysis

BACKGROUND Spotty calcification is a morphological characteristic of a vulnerable plaque phenotype. While this calcium pattern is considered an active process, promoted by inflammation, it is unknown whether spotty calcification associates with development of microstructures observed in vulnerable plaques. As frequency-domain optical coherence tomography (FD-OCT) enables visualization of microstructures associated with plaque vulnerability, we investigated the association between spotty calcification and plaque microstructures by using FD-OCT. METHODS A total of 300 patients with stable coronary artery disease (CAD), having clinical indication for percutaneous coronary intervention (PCI), were analyzed. Totally 280 non-culprit lipid plaques within the target vessel requiring PCI were evaluated by FD-OCT. Spotty calcification was defined as a presence of lesion <4 mm in length, containing an arc of calcification <90° on FD-OCT. Plaque microstructures were compared in non-culprit lipid-rich plaques with and without spotty calcification. RESULTS Spotty calcification was observed in 39.6% of non-culprit lipid-rich plaques, with 30.6% of these plaques demonstrating multiple spotty calcifications. Plaques containing spotty calcification exhibited a greater lipid index (= averaged lipid arc × lipid length); 1,511.8±1,522.3 vs. 815.2±1,040.3 mm°, P<0.0001), thinner fibrous caps (89.0±31.6 vs. 136.5±32.5 µm, P=0.002) and a higher prevalence of microchannels (45.9% vs. 17.7%, P=0.007). A significant association was observed between the number of spotty calcifications per plaque and fibrous cap thickness (r=-0.40, P=0.006). Increased number of spotty calcification was also associated with a higher prevalence of microchannel within plaques (P=0.01). CONCLUSIONS In patients with stable CAD requiring PCI, the presence of spotty calcification imaged by FD-OCT was associated with features of greater plaque vulnerability.

Low-density lipoprotein cholesterol levels and lipid-modifying therapy prescription patterns in the real world: An analysis of more than 33,000 high cardiovascular risk patients in Japan

BACKGROUND AND AIMS Low-density lipoprotein cholesterol (LDL-C) is a key modifiable risk factor in the development of cardiovascular (CV) disease. In 2012, the Japan Atherosclerosis Society (JAS) issued guidelines recommending statins as first-line pharmacotherapy for lowering LDL-C in patients at high risk for CV events. This study assessed achievement of recommended LDL-C goals and lipid-modifying therapy (LMT) use in a high CV risk population in Japan. METHODS Patients from the Medical Data Vision (MDV) database, an electronic hospital-based claims database in Japan, who met the following inclusion criteria were included in this study: LDL-C measurement in 2013; ≥20 years of age; ≥2 years representation in the database; and a high CV risk condition (recent acute coronary syndrome (ACS), other coronary heart disease (CHD), ischemic stroke, peripheral arterial disease (PAD) or diabetes). LDL-C goal attainment was assessed based on LDL-C targets in the JAS guidelines. RESULTS A total of 33,325 high CV risk patients met the inclusion criteria. Overall, 68% of the cohort achieved guideline recommended LDL-C targets, with only 42% receiving current treatment with statins. Attainment of LDL-C goals was 68% for ACS, 55% for CHD, and 80% each for ischemic stroke, PAD, and diabetes patients. Concomitant use of non-statin LMTs was low. CONCLUSIONS In a high CV risk population in a routine care setting in Japan, guideline recommended LDL-C goal attainment and utilization of statins and other LMT was low. In addition, physicians appeared to be more likely to consider the initiation of statins in patients with higher baseline LDL-C levels.

Cholesterol crystals associate with coronary plaque vulnerability in vivo.

The high local concentration of cholesterol in foam cells has been reported to formulate cholesterol crystals, which trigger a local inflammatory response [(1)][1]. Intracellular crystals also induce apoptosis of foam cells, leading to further attraction of macrophages and development of a lipid-

Epanova® and hypertriglyceridemia: pharmacological mechanisms and clinical efficacy

While LDL-cholesterol lowering has become the cornerstone of cardiovascular risk reduction strategies, considerable interest in additional targeting of hypertriglyceridemia continues. While ω-3 fatty acids are commonly used in clinical practice for triglyceride lowering, no large-scale clinical trial evaluating their impact on clinical events has been performed. As a result, there remains a lack of consensus with regards to their optimal clinical use. Epanova(®) (Omthera Pharmaceuticals Inc., NJ, USA) is a novel ω-3 free fatty acid formulation, developed to maximize eicosapentenoic acid and docosahexenoic acid bioavailability with low-fat diets, suggesting a potential therapeutic advantage compared with ω-3-acid ethyl esters in the treatment of patients with hypertriglyceridemia. Additional human studies are needed to define more clearly the cellular and molecular basis for the triglyceride-lowering effects of Epanova and this drugs favorable cardiovascular effects, particularly in patients with hypertriglyceridemia.

Progression of coronary atherosclerosis in African-American patients

BACKGROUND African-Americans with coronary artery disease (CAD) demonstrate worse clinical outcomes than Caucasians. While this is partly due to a lack of accessibility to established therapies, the mechanisms underlying this difference remain to be elucidated. We aimed to characterize the progression of coronary atherosclerosis in African-Americans with CAD. METHODS 3,479 patients with CAD underwent serial intravascular ultrasound (IVUS) imaging to evaluate atheroma progression in 7 clinical trials of anti-atherosclerotic therapies. Risk factor control and atheroma progression were compared between African-Americans (n=170) and Caucasians (n=3,309). RESULTS African-Americans were more likely to be female (51.8% vs. 28.1%, P<0.001), have a higher body mass index (32.8±6.0 vs. 31.3±5.8 kg/m(2), P=0.002) and greater history of hypertension (85.9% vs. 78.8%, P=0.02), diabetes (41.8% vs. 30.6%, P=0.002) and stroke (12.9% vs. 3.0%, P<0.001). Despite a high use of anti-atherosclerotic medications (93% statin, 89% aspirin, 79% β-blocker, 52% ACE inhibitor), African-Americans demonstrated higher levels of LDL-C (2.4±0.7 vs. 2.2±0.7 mmol/L, P=0.006), CRP (2.9 vs. 2.0 mg/dL, P<0.001) and systolic blood pressure (133±15 vs. 129±13 mmHg, P<0.001) at follow-up. There was no significant difference in atheroma volume at baseline (189.0±82.2 vs. 191.6±83.3 mm(3), P=0.82) between two groups. Serial evaluation demonstrated a greater increase in atheroma volume in African-Americans (0.51±2.1 vs. -3.1±1.7 mm(3), P=0.01). This difference persisted with propensity matching accounting for differences in risk factor control (0.1±2.1 vs. -3.7±1.7 mm(3), P=0.02). CONCLUSIONS African-Americans with CAD achieve less optimal risk factor control and greater atheroma progression. These findings support the need for more intensive risk factor modification in African-Americans.

Aortic atheroma burden predicts acute cerebrovascular events after transcatheter aortic valve implantation: insights from volumetric multislice computed tomography analysis.

AIMS Embolisation of atheromatous debris during catheter manipulation is considered to underlie acute cerebrovascular events (CVE) after transcatheter aortic valve implantation (TAVI). However, the relationship between aorta atheroma burden and acute CVE after TAVI has not been established. We investigated the impact of aorta atheroma burden on acute CVE. METHODS AND RESULTS Preoperative multislice computed tomographic (MSCT) images in 278 patients receiving TAVI were analysed. Total atheroma volume (TAV) was calculated by measuring aorta vessel and lumen areas in every 1 mm cross-sectional image. Acute CVE was observed in 16 patients. Patients having acute CVE were more likely to have a prior CVE (p=0.002), and to exhibit greater TAV in the ascending aorta (12.8±3.5 vs. 7.0±2.1 cm3, p<0.001) and the aortic arch (3.1±1.6 vs. 1.2±0.2 cm3, p<0.001). TAV in the ascending aorta >10.3 cm3 and in the aortic arch >2.9 cm3 predicted acute CVE. The incidence of acute CVE was highest (36.4%) if patients had a prior CVE and TAV in the ascending aorta and the aortic arch above cut-offs. CONCLUSIONS Patients with acute CVE after TAVI had greater aorta atheroma burden. Our findings might underscore preoperative MSCT analysis of aorta atherosclerosis to identify high-risk patients for acute CVE, who might require an embolic protection device during TAVI.

Effect of alirocumab on coronary atheroma volume in Japanese patients with acute coronary syndromes and hypercholesterolemia not adequately controlled with statins: ODYSSEY J-IVUS rationale and design

BACKGROUND Serial intravascular ultrasound (IVUS) imaging can be used to evaluate the effect of cholesterol-lowering on coronary atheroma progression and plaque volume, with evidence of potential incremental effects with more aggressive lipid-lowering treatments. Alirocumab is a highly specific, fully human monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9). This study will investigate the effect of alirocumab on coronary artery plaque volume in Japanese patients with a recent acute coronary syndrome (ACS) and hypercholesterolemia while on stable statin therapy. METHODS ODYSSEY J-IVUS is a phase IV, open-label, randomized, blinded IVUS analysis, parallel-group, multicenter study in Japanese adults recently hospitalized for an ACS and who have elevated low-density lipoprotein cholesterol (LDL-C) values [≥100mg/dL (2.6mmol/L)] at ACS diagnosis and suboptimal LDL-C control on stable statin therapy. Patients will be randomized (1:1) to receive alirocumab or standard-of-care (SOC). The alirocumab arm will receive alirocumab 75mg every 2 weeks (Q2W) added to statin therapy (atorvastatin ≥10mg/day or rosuvastatin ≥5mg/day), with a dose increase to 150mg Q2W in patients whose LDL-C value remains ≥100mg/dL at week 12. The SOC arm will receive atorvastatin ≥10mg/day or rosuvastatin ≥5mg/day, with dose adjustment to achieve LDL-C <100mg/dL. Post-treatment IVUS imaging will be done at week 36±2. The primary objective is to compare the effect of alirocumab versus SOC on coronary atheroma progression (percent change in normalized total atheroma volume) after 9 months of treatment. CONCLUSION ODYSSEY J-IVUS will provide insights into the effect of alirocumab on coronary atherosclerotic plaque volume in patients with a recent ACS and hypercholesterolemia while on stable statin therapy. ClinicalTrials.gov number: NCT02984982.

Exploration into lipid management and persistent risk in patients hospitalised for acute coronary syndrome in Japan (EXPLORE-J): protocol for a prospective observational study

Introduction The present study is the largest registry study ever conducted in Japan exploring the prevalence of familial hypercholesterolaemia (FH) among patients with acute coronary syndrome (ACS). Our study aims to (1) evaluate the status of lipid management and the subsequent risk of major cardiovascular events following hospitalisation of Japanese patients with ACS in real-world clinical practice; (2) determine the proportion of Japanese patients with ACS who achieve the lipid management goal and have a reduction of event risks with strict lipid management (low-density lipoprotein-cholesterol <1.81 mmol/L); (3) determine the prevalence of FH and (4) investigate the clinical significance of proprotein convertase subtilisin kexin 9 (PCSK9) level. Methods and analysis We will conduct a multicentre, prospective, observational study of approximately 2000 Japanese patients with ACS with/without FH hospitalised between April 2015 and August 2016. The primary end point is the incidence of major adverse cardiovascular events (MACEs) after initial hospitalisation. The secondary end points are (1) MACE developed from visit 1 to visit 2 (day 30); (2) MACE developed from visit 2 (day 30) to visit 5 (day 730); (3) treatment rate by lipid-lowering therapies (any statin or intensive, PCSK9 inhibitor, fibrates and ezetimibe); (4) incidence of events by the addition of the following outcomes to the primary end point: coronary revascularisation due to myocardial ischaemia, revascularisation other than coronary artery, inpatient treatment for occurrence or exacerbation of heart failure, transient ischaemic attack, acute arterial occlusion, central retinal artery occlusion and other adverse events prolonging or requiring hospitalisation and (5) proportion of subjects achieving target lipid levels. Ethics and dissemination The study protocol was submitted to the ethical review committee of each participating centre for approval. Participation in the study is voluntary and anonymous. The study findings will be disseminated in international peer-reviewed journals and presented at relevant conferences. Clinical trial registration UMIN000018946.