Coronary Artery Plaque Regression by a PCSK9 Antibody and Rosuvastatin in Double-heterozygous Familial Hypercholesterolemia with an LDL Receptor Mutation and a PCSK9 V4I Mutation.

The low-density lipoprotein-cholesterol (LDL-C) level of a 38-year-old man diagnosed with acute coronary syndrome was 257 mg/dL. The administration of a proprotein convertase subtilisin-kexin type 9 (PCSK9) antibody in addition to rosuvastatin plus ezetimibe was initiated, reducing his LDL-C level to 37 mg/dL. A genetic analysis revealed both an LDL receptor (LDLR) mutation and a PCSK9 V4I mutation. Nine months after revascularization, intravascular ultrasound revealed plaque regression in the coronary arteries. LDLR/PCSK9 mutation carriers are prone to coronary artery disease. Intensive LDL-C lowering by including PCSK9 antibody was associated with coronary plaque regression, suggesting the expectation of prognosis improvement.

Complete response to rivaroxaban in a case of invaginated thrombus thought to have extended through a patent foramen ovale with an accompanying pulmonary embolism.

Occurrence of paradoxical embolisms caused by deep venous thrombosis (DVT) is often encountered in the clinical setting. However, a thrombus that is invaginated from the right atrium into the left atrium (an impending paradoxical embolism) is rare. We report a case of an 80-year-old woman who had the complication of an impending paradoxical embolism and a pulmonary embolism. Because an indication of new anticoagulants was expanded to treatment of venous thromboembolism and oral administration became available, we initially administered edoxaban, which did not cause the thrombus to disappear. Therefore, we switched to rivaroxaban, which resulted in successful elimination of the thrombus. Our findings indicate the differences in effects between each novel oral anticoagulant. .

Effect of a hydrophilic and a hydrophobic statin on cardiac salvage after ST-elevated acute myocardial infarction - a pilot study.

OBJECTIVE: Early statin therapy after acute coronary syndrome reduces atherothrombotic vascular events. This study aimed to compare the effects of hydrophilic and hydrophobic statins on myocardial salvage and left ventricular (LV) function in patients with ST-elevated myocardial infarction (STEMI). METHODS: Seventy-five STEMI patients who had received emergency reperfusion therapy were enrolled and randomized into the hydrophilic statin group (rosuvastatin; 5 mg/day, n = 38) and hydrophobic statin group (atorvastatin; 10 mg/day, n = 37) for 6 months. LV ejection fraction (LVEF), and B-type natriuretic peptide (BNP) and co-enzyme Q10 (CoQ10) levels were measured at baseline and the end of treatment. The myocardial salvage index was assessed by single photon emission computed tomography with (123-)I-ß-methyl-iodophenylpentadecanoic acid (ischemic area-at-risk at onset of STEMI: AAR) and (201-)thallium scintigraphy (area-at-infarction at 6 months: AAI) [myocardial salvage index = (AAR-AAI) × 100/AAR (%)]. RESULTS: Onset-to-balloon time and maximum creatine phosphokinase levels were comparable between the groups. After 6 months, rosuvastatin (-37.6% ± 17.2%) and atorvastatin (-32.4% ± 22.4%) equally reduced low-density lipoprotein-cholesterol (LDL-C) levels (p = 0.28). However, rosuvastatin (+3.1% ± 5.9%, p < 0.05), but not atorvastatin (+1.6% ± 5.7%, p = 0.15), improved LVEF. Rosuvastatin reduced BNP levels compared with atorvastatin (-53.3% ± 48.8% versus -13.8% ± 82.9%, p < 0.05). The myocardial salvage index was significantly higher in the rosuvastatin group than the atorvastatin group (78.6% ± 29.1% versus 52.5% ± 38.0%, p < 0.05). CoQ10/LDL-C levels at 6 months were increased in the rosuvastatin group (+23.5%, p < 0.01) and percent changes in CoQ10/LDL-C were correlated with the myocardial salvage index (r = 0.56, p < 0.01). CONCLUSION: Rosuvastatin shows better beneficial effects on myocardial salvage than atorvastatin in STEMI patients, including long-term cardiac function, associated with increasing CoQ10/LDL-C. CLINICAL TRIAL REGISTRATION: URL http://www.umin.ac.jp/ctr/index.htm Unique Identifier: UMIN000003893.

Impact of CYP3A5 polymorphism on platelet reactivity at percutaneous coronary intervention and after 9 months of aspirin and clopidogrel therapy in Japanese patients with coronary artery disease.

BACKGROUND: High residual platelet reactivity in patients receiving clopidogrel is associated with an increased risk of a cardiovascular event after coronary stenting. The aim of our study was to evaluate the impact of the cytochrome P450 (CYP) 3A5 and CYP2C19 polymorphisms on platelet reactivity during dual antiplatelet therapy. METHODS: We determined the CYP2C19 and CYP3A5 genotypes of 101 angina patients (65 male patients, mean age 64 years) receiving dual antiplatelet therapy with aspirin and clopidogrel and evaluated the effect of these polymorphism on platelet reactivity at the early and late phases of treatment using a conventional light transmission aggregometry. Early and late phases were defined as 24 h after the loading dose and after 9 months on a maintenance dose of 75 mg daily, respectively. RESULTS: The distribution of the CYP2C19 genotype was 30 % in extensive metabolizers (EM; CYP2C19*1/*1), 46 % in intermediate metabolizers (IM; *1/*2, *1/*3), and 25 % in poor metabolizers (PM; *2/*2, *2/*3, *3/*3). Platelet reactivity levels in during the early and late phases were 3,793 ± 1,476 and 2,960 ± 1,410, respectively, in EM, 4,706 ± 1,417 and 3,239 ± 1,479, respectively, in IM, and 5,402 ± 776 and 4,736 ± 1,356 aggregation units (AU)•min, respectively in EM. The distribution of the CYP3A5 genotype was 33 % in patients carrying the wild-type or one loss-of-function allele (Expressor phenotype; *1/*1 and *1/*3, respectively) and 67 % in those carrying two loss-of-function alleles (Non-expressor; *3/*3). In total, eight patients were EM+Expressor, 22 were EM+Non-expressor, 18 were IM+Expressor, 28 were IM+Non-expressor, eight were PM+Expressor, and 17 were PM+Non-expressor. In the late phase of PM with the CYP2C19 polymorphism, the levels of platelet reactivity according to CYP3A5 genotype were 3,963 ± 1,436 and 5,100 ± 1,190 AU•min in Expressor and Non-expressor, respectively (P < 0.05), however, there was no difference in platelet reactivity between Expressor and Non-expressor in EM and IM. CONCLUSIONS: Our results suggest that antiplatelet response to clopidogrel in the late phase depends on the CYP3A5 polymorphism in PM with CYP2C19.

Intravascular ultrasound morphology of culprit lesions and clinical demographics in patients with acute coronary syndrome in relation to low-density lipoprotein cholesterol levels at onset.

Despite current standards of care aimed at achieving targets for low-density lipoprotein cholesterol (LDL-C), many patients remain at high residual risk of cardiovascular events. We sought to assess the LDL-C-dependent differences in culprit intravascular ultrasound (IVUS) morphologies and clinical characteristics in patients with acute coronary syndrome (ACS). Eighty-six consecutive ACS patients whose culprit lesions imaged by preintervention IVUS were divided into two groups based on the fasting LDL-C level on admission: a low-LDL-C group (LDL-C <2.6 mmol/l, n = 45) and a high-LDL-C group (LDL-C ≥2.6 mmol/l, n = 41). Patients with stable angina with LDL-C <2.6 mmol/l (n = 30) were also enrolled as an age- and gender-matched control. The low-LDL-C ACS group was significantly older (72 ± 12 vs 64 ± 14 years, P = 0.007) and more diabetic (47 % vs 15 %, P = 0.001). Importantly, IVUS morphologies were comparable between low- and high-LDL-C ACS groups (all P not significant), whereas culprit plaque was more hypoechoic and less calcified in the low-LDL-C ACS group than in the low-LDL-C stable angina group. Furthermore, compared with the low-LDL-C ACS nondiabetic group, the low-LDL-C ACS diabetic group was more obese, more triglyceride rich (1.3 ± 0.6 vs 0.9 ± 0.4 mmol/l, P = 0.003), and more endothelially injured, but no different for the culprit IVUS morphologies. In multivariate analysis, diabetes was independently associated with a low LDL-C level on admission in patients with ACS. There was no relationship between the LDL-C level at onset and culprit-plaque IVUS morphologies in ACS patients, although culprit plaque in the low-LDL-C ACS group was more vulnerable than in the low-LDL-C stable angina group. In patients with low-LDL-C levels, diabetes with atherogenic dyslipidemia might be the key residual risk.

Premenopausal woman with acute myocardial infarction caused by spontaneous coronary artery dissection and potential association with coronary vasospasm.

A 45-year-old premenopausal woman presented with acute myocardial infarction (MI). An intravascular ultrasound (IVUS) revealed that her distal right coronary artery was occluded by spontaneous coronary artery dissection (SCAD). She did not have any specific condition related to SCAD. At follow-up cardiac catheterization, an acetylcholine provocation test was applied to examine the etiology of SCAD, and definitive coronary vasospasm was induced with chest symptoms and significant electrocardiographic change. A Ca-channel blocker was administered and since then chest pain has subsequently so far been relieved. The current case suggests the significance of the IVUS in detecting etiology of MI in younger patients and the potential association between SCAD and coronary vasospasm.

Clinical outcomes following coronary stenting in Japanese patients treated with and without proton pump inhibitor.

BACKGROUND: The aim of this study was to examine the effect of proton-pump inhibitor (PPI) on clinical outcomes in Japanese patients who undergo coronary stent implantation. METHODS AND RESULTS: A total of 1,270 patients (males 915, 69 years) were enrolled and dual antiplatelet therapy of aspirin and a thienopyridine derivative was prescribed (clopidogrel 630, ticlopidine 640). Patients were divided into 2 groups treated with or without PPI. PPI was administered in 331 cases (26%), and non-PPI in 939 (74%). There were no significant differences in cardiovascular death (PPI vs. non-PPI: 5 vs. 11 cases), nonfatal myocardial infarction (3 vs. 5), and stroke (3 vs. 16) between PPI and non-PPI groups, but the ratio of gastrointestinal events had a higher tendency in non-PPI group compared with PPI group (1 vs. 17, P=0.08). In subgroup analysis of patients taking clopidogrel, or patients with acute coronary syndrome, there was no significant difference in the ratio of cardiovascular events (7 vs. 16, 6 vs. 17, NS). The non-PPI group had a tendency of an increased risk of gastrointestinal events compared with the PPI group (0 vs. 9, P=0.06; 1 vs. 7, P=0.14). CONCLUSIONS: In contrast to the negative drug interaction of PPI reported elsewhere, in the present study the intake of PPI was not associated with an increased risk for adverse clinical outcomes in patients treated with stents.

Current status and prospects of antiplatelet therapy in percutaneous coronary intervention in Japan: focus on adenosine diphosphate receptor inhibitors.

Dual antiplatelet therapy with aspirin and clopidogrel is routinely used to prevent thrombotic events in patients with acute coronary syndrome undergoing percutaneous coronary intervention (PCI) in Japan. However, these agents have various limitations and some patients will experience further cardiovascular events. The purpose of this article is to review the antiplatelet agents currently used in patients undergoing PCI in Japan, to discuss the issues and limitations associated with these antiplatelet agents, and to characterize new antiplatelet agents currently under investigation in Japan. Particular emphasis is placed on the novel thienopyridine prasugrel, and the potential this drug has for overcoming the issues associated with other antiplatelet agents.

Impact of CYP2C19 polymorphism on residual platelet reactivity in patients with coronary heart disease during antiplatelet therapy.

BACKGROUND AND PURPOSE: CYP2C19*2 loss-of-function allele in Caucasians may be associated with wide interindividual variability in platelet response to clopidogrel, and the incidence of gene mutation varies with racial differences, especially between Asians and Caucasians. The aim was to examine the impact of CYP2C19 genotype on the residual platelet reactivity in Japanese patients with coronary heart disease (CHD) during antiplatelet therapy. METHODS AND RESULTS: We measured the CYP2C19 genotype and platelet aggregation in 201 patients with stable CHD. Moreover, we examined the relation of CYP2C19 polymorphism to cardiovascular events in 98 patients treated with stent implantation. The distribution of CYP2C19 genotype was 37%, 33%, 11%, 11%, 7%, and 1% in CYP2C19*1/*1, *1/*2, *1/*3, *2/*2, *2/*3, and *3/*3, respectively. Residual platelet reactivity was lower in patients during dual antiplatelet therapy (DAT) than in those with aspirin (3975 ± 1569 aggregation units minute (AU min) vs 5850 ± 938 AU min, p<0.05). In the DAT group, the platelet reactivity decreased significantly in the wild-type homozygotes (CYP2C19*1/*1), subsequently in the *2, or *3 heterozygotes (*1/*2, *1/*3), and was not well inhibited in the *2, and/or *3 homozygotes (*2/*2, *2/*3, *3/*3; 3194 ± 1570 AU min, 4148 ± 1400 AU min, and 5088 ± 1080 AU min, respectively). However, when the duration of DAT was used to divide subjects into 2 groups, <7 days, and >7 days, patients carrying the variant allele showed significantly decreased platelet reactivities at >7 days compared with those at <7 days. Moreover, the incidence of cardiovascular events was higher in patients carrying at least one variant allele than in wild-type homozygotes. CONCLUSIONS: CYP2C19 polymorphism may be associated with high residual platelet reactivity and the occurrence of cardiovascular events.

Effect of edaravone on plasma monocyte chemoattractant protein-1 levels in patients with acute myocardial infarction.

BACKGROUND: Monocyte chemoattractant protein-1 (MCP-1) plays an important role in the pathogenesis of acute coronary syndrome. We have recently demonstrated that the administration of edaravone before reperfusion attenuated reperfusion injury in patients with acute myocardial infarction (AMI). METHODS: Plasma MCP-1 levels were measured in 45 consecutive patients with AMI (edaravone group, n=25; control group, n=20). In the edaravone group, 30 mg edaravone was intravenously infused just before reperfusion. Plasma samples were obtained before and at 24h, 3, 5, 7, and 14 days after reperfusion. Cardiovascular events were defined as cardiac death, subacute thrombosis, or fatal arrhythmia. Heart failure requiring rehospitalization was evaluated at 12 months after reperfusion. RESULTS: Plasma MCP-1 levels were not different between the two groups before reperfusion. Compared with the placebo group, the edaravone group had statistically lower maximum creatine kinase-MB levels (218±31 IU/l versus 145±21 IU/l, p<0.05) and plasma MCP-1 levels on day 3 after reperfusion (873±118 pg/ml versus 516±66 pg/ml, p<0.05). Heart failure requiring rehospitalization occurred in four patients in the control group, but did not occur in the edaravone group (p<0.05). At 12 months after reperfusion, left ventricular ejection fraction was statistically higher in the edaravone group than in the control group (62±2% versus 54±3%, p<0.05). CONCLUSION: Edaravone suppressed plasma MCP-1, improved left ventricular ejection fraction, and reduced rehospitalization due to heart failure. Suppression of plasma MCP-1 level by edaravone might induce better prognosis for AMI patients.