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.

Neointimal tissue component assessed by tissue characterization with 40 MHz intravascular ultrasound imaging: comparison of drug-eluting stents and bare-metal stents.

OBJECTIVES: The present study used iMap IVUS system to compare neointimal tissue components between DES and bare-metal stents (BMSs). BACKGROUND: Drug-eluting stents (DESs) can cause impaired arterial healing, which constitutes the most important pathological substrate underlying late DES thrombosis. Intravascular ultrasound (IVUS)-based tissue characterization allows for the in vivo identification of neointimal tissue components. METHODS AND RESULTS: Follow-up IVUS data after coronary stenting (9.8 ± 9.4 months from index procedures) was obtained from consecutive 61 lesions (34 in DES, 27 in BMS). The iMap tissue components (fibrotic, lipidic, necrotic, and calcified) were measured in every recorded frame and expressed as percentages of mean neointimal cross-sectional area for the stented segment. Patients' characteristics were comparable between DES and BMS. When compared with BMSs, smaller (2.9 ± 0.4 mm vs. 3.2 ± 0.4 mm, P = 0.004) and longer (34 ± 18 mm vs. 26 ± 14 mm, P = 0.03) DESs were implanted. When compared with BMS group, minimum lumen area at follow-up was significantly greater in DES group (3.9 ± 1.8 mm(2) vs. 3.1 ± 1.5 mm(2) , P < 0.04), mainly attributable to suppression of neointimal hyperplasia (1.7 ± 0.8 mm(2) vs. 3.1 ± 1.5 mm(2) , P < 0.0001). The iMap analyses showed that neointima after DES placement was composed of smaller fibrotic component (67 ± 8% vs. 78 ± 7%, P < 0.0001), larger necrotic (14 ± 4% vs. 9 ± 3%, P < 0.0001) and calcified (15 ± 6% vs. 7 ± 4%, P < 0.0001) components compared with BMS. Logistic regression analysis showed that only intra-DES neointima was a significant predictor of necrotic neointima at follow-up. CONCLUSIONS: DES implantation would be associated with iMap-derived necrotic and less-fibrotic neointimal formation. In vivo iMap evaluation of neointimal tissue may provide useful information in detecting impaired healing after stenting.

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.

Impact of CYP2C19 polymorphism and proton pump inhibitors on platelet reactivity to clopidogrel and clinical outcomes following stent implantation.

BACKGROUND: The response to clopidogrel, and some kind of the drug interaction are multifactorial. METHODS AND RESULTS: We enrolled 174 consecutive patients and determined CYP2C19 genotypes, measured platelet aggregation, and assessed the relationship between CYP2C19 genotype and platelet reactivity 24hours after clopidogrel administration, and the risk of cardiovascular events over 18months follow-up. A sub analysis examined the impact of rabeprazole, a proton pump inhibitor (PPI) less affected by CYP2C19. The CYP2C19 genotype was extensive metabolizer (EM) in 36%, intermediate metabolizer (IM) in 45%, and poor metabolizer (PM) in 19%. Platelet reactivity was significantly lower in the EM group than in the IM and PM groups (EM, IM, PM: 3560±1404, 4203±1302, 5084±1007AU•min, P<0.05). The cardiovascular event rate was higher in the IM and PM groups than in the EM group (12.7% and 12.5% vs 1.6%; Hazard ratio for IM 10.6, P=0.029; for PM 11.3, P=0.040). No differences were seen between patients taking (N=50) and not taking (N=124) rabeprazole in residual platelet aggregation (4407±1360 vs 4048±1394, AU•min, P=0.2782), or in cardiovascular events (10.0% vs 8.1%, HR 0.97, P=0.97). CONCLUSIONS: CYP2C19 genotype is associated with an increased risk of cardiovascular events following stent implantation in Japanese patients.

Impact of CYP2C19 polymorphism on clinical outcome following coronary stenting is more important in non-diabetic than diabetic patients.

OBJECTIVE: The aim of this study was to examine the impact of CYP2C19 genotype on clinical outcome in coronary artery disease (CAD) patients with or without diabetes mellitus (DM). METHODS: CYP2C19 polymorphism and DM are associated with increased risk of cardiovascular events during antiplatelet therapy following stent implantation. Platelet reactivity during clopidogrel therapy and CYP2C19 polymorphism were measured in 519 CAD patients (males 70%, age 69 years) treated with stent placement. Patients were divided into two groups; DM (n=249), and non-DM (n=270), and clinical events were evaluated according to the carrier state, which included at least one CYP2C19 loss-of-function allele. RESULTS: The level of platelet reactivity and incidence of cardiovascular events were significantly different between Carriers and non-Carriers of the non-DM (platelet reactivity: 4501+/-1668 versus 3691+/-1714AU min, P<0.01; events, 32/178 versus 2/92, P<0.01, respectively), however, there was no difference in clinical outcome in the DM group (events, 34/168 versus 14/81, respectively, P=0.57). Multivariate analysis identified CYP2C19 loss-of-function allele carriage as an independent predictor of cardiovascular events in non-DM, but not in DM (non-DM, HR 7.180, 95% CI, 1.701 to 30.298, P=0.007; DM, HR 1.374, 95% CI, 0.394 to 4.792, P=0.618). CONCLUSION: The impact of CYP2C19 polymorphism on clinical outcome seems to be more significant in non-DM compared with DM in patients with coronary stents.

A case of human immunodeficiency virus-related heart failure resembling dilated cardiomyopathy but accompanied by high cardiac output.

A 34-year-old man presented with heart failure (HF). He suffered opportunistic infections and was shown to be human immunodeficiency virus (HIV)-positive (viral load: 156,013 copies/mL) and have low CD4 lymphocytes (3/mm3), so he was initially treated for the opportunistic infections. Initial investigations showed high elevation of brain natriuretic peptide (BNP: 969 pg/mL). Transthoracic echocardiography showed an enlarged left ventricle (LV: 70 mm), a reduced LV ejection fraction (EF: 19%), but no LV hypertrophy or significant valvular diseases. After treatments for the infections, we started standard HF medications. Cardiac catheterization, after recovery from the opportunistic infections with negative inflammatory markers, showed no significant coronary stenosis, and endomyocardial biopsy did not show findings of myocarditis, without HIV structural protein on immunohistochemistry. Despite reduced EF, the cardiac output was elevated at 7.1 l/min [cardiac index (CI): 4.3 l/min/m2] and the systemic vascular resistance index was decreased at 1358 dynes s/cm5 m2. Hematologists began anti-retroviral therapy; the viral load was gradually reduced to negative, and the CD4 count was increased to 50/mm3 at Day 182. EF was accordingly improved up to 54%, but the cardiac output decreased to a normal level at 3.9 l/min (CI: 2.4 l/min/m2), leading to normalization of plasma BNP (<5 pg/mL). This case indicates that high cardiac output might be involved in the pathogenic mechanisms of HIV-related HF. .

Comprehensive analysis of intravascular ultrasound and angiographic morphology of culprit lesions between ST-segment elevation myocardial infarction and non-ST-segment elevation acute coronary syndrome.

BACKGROUND: Some plaques lead to ST-segment elevation myocardial infarction (STEMI), whereas others cause non-ST-segment elevation acute coronary syndrome (NSTEACS). We used angiography and intravascular ultrasound (IVUS) to investigate the difference of culprit lesion morphologies in ACS. METHODS: Consecutive 158 ACS patients whose culprit lesions were imaged by preintervention IVUS were enrolled (STEMI=81; NSTEACS=77). IVUS and angiographic findings of the culprit lesions, and clinical characteristics were compared between the groups. RESULTS: There were no significant differences in patients' characteristics except for lower rate of statin use in patients with STEMI (20% vs 44%, p=0.001). Although angiographic complex culprit morphology (Ambrose classification) and thrombus were more common in STEMI than in NSTEACS (84% vs 62%, p=0.002; 51% vs 5%, p<0.0001, respectively), SYNTAX score was lower in STEMI (8.6 ± 5.4 vs 11.5 ± 7.1, p=0.01). In patients with STEMI, culprit echogenicity was more hypoechoic (64% vs 40%, p=0.01), and the incidence of plaque rupture, attenuation and "microcalcification" were significantly higher (56% vs 17%, p<0.0001; 85% vs 69%, p=0.01; 77% vs 61%, p=0.04, respectively). Furthermore, the maximum area of ruptured cavity, echolucent zone and arc of microcalcification were significantly greater in STEMI compared with NSTEACS (1.80 ± 0.99 mm(2) vs 1.13 ± 0.86 mm(2), p=0.006; 1.52 ± 0.74 mm(2) vs 1.21 ± 0.81 mm(2), p=0.004; 99.9 ± 54.6° vs 77.4 ± 51.2°, p=0.01, respectively). Quantitative IVUS analysis showed that vessel and plaque area were significantly larger at minimum lumen area site (16.6 ± 5.4 mm(2) vs 14.2 ± 5.5 mm(2), p=0.003; 13.9 ± 5.1 mm(2) vs 11.6 ± 5.2 mm(2), p=0.003, respectively). CONCLUSION: Morphological feature (outward vessel remodeling, plaque buildup and IVUS vulnerability of culprit lesions) might relate to clinical presentation in patients with ACS.

Clinical features and prognosis of patients with coronary spasm-induced non-ST-segment elevation acute coronary syndrome.

BACKGROUND: The prevalence, clinical features, and long-term outcome of patients with non-ST-segment elevation acute coronary syndrome (NSTE ACS) associated with coronary spasm are not fully investigated. METHODS AND RESULTS: This observational multicenter study enrolled 1601 consecutive patients with suspected NSTE-ACS who underwent cardiac catheterization between January 2001 and December 2010. A culprit lesion was found in 1152 (72%) patients. In patients without a culprit lesion, the acetylcholine provocation test was performed in 221 patients and was positive in 175 patients. In the other patients, coronary spasm was verified in 145 patients during spontaneous attack. Spasm-induced NSTE-ACS was diagnosed in 320 (20%) patients. Multivariable analysis identified age <70 years (odds ratio [OR] 2.19, 95% CI 1.58 to 3.04), estimated glomerular filtration rate >60 mL/min per 1.73 m(2) (OR 1.72, 95% CI 1.16 to 2.56), and lack of hypertension (OR 2.55, 95% CI 1.90 to 3.41), dyslipidemia (OR 2.76, 95% CI 2.05 to 3.73), diabetes mellitus (OR 2.49, 95% CI 1.78 to 3.48), previous myocardial infarction (OR 5.37, 95% CI 2.89 to 10.0), and elevated cardiac biomarkers (OR 2.84, 95% CI 2.11 to 3.83) as significant correlates of spasm-induced NSTE-ACS (P<0.01 for all variables). Transient ST-segment elevation during spontaneous attack (variant angina) was observed in 119 patients with spasm-induced NSTE-ACS. Variant angina was more common in nondyslipidemic men among patients with spasm-induced NSTE-ACS. CONCLUSIONS: The study showed frequent involvement of coronary spasm in the pathogenesis of NSTE-ACS. Variant angina was observed in one third of patients with spasm-induced NSTE-ACS. Coronary spasm should be considered even in patients with less coronary risk factors and nonobstructive coronary arteries.

Management of intra-aortic balloon counterpulsation by argatroban anticoagulation in a patient with a history of heparin-induced thrombocytopenia.

Intra-aortic balloon counterpulsation (IABP) has been used in various cardiovascular conditions including cardiogenic shock. Prophylactic systemic heparinization has been commonly utilized to prevent thrombotic complications. There are a number of anticoagulants in addition to heparin; however, there is little consensus and few data to support the safety of alternative anticoagulation during IABP management. We report here on the case of a 47-year-old woman with cardiogenic shock. She had a medical history of heparin-induced thrombocytopenia (HIT) type II and soon after admission she deteriorated into cardiogenic shock of unknown etiology. This patient survived by IABP circulatory support with alternative argatroban anticoagulant therapy; and there were no signs of thrombus or thromboembolism in this patient or on the catheter itself. Our report suggests that alternative anticoagulation by argatroban may be a safe and effective therapeutic option in seriously ill patients requiring IABP support and nonheparin anticoagulation.