Sex differences in the impact of CYP2C19 polymorphisms and low-grade inflammation on coronary microvascular disorder.

Categorization as a cytochrome P-450 (CYP) 2C19 poor metabolizer (PM) is reported to be an independent risk factor for cardiovascular disease. It is correlated with an increase in the circulating levels of high-sense C-reactive protein (hs-CRP) in women only, although its role in coronary microcirculation is unclear. We examined sex differences in the impact of the CYP2C19 genotype and low-grade inflammation on coronary microvascular disorder (CMVD). We examined CYP2C19 genotypes in patients with CMVD (n = 81) and in healthy subjects as control (n = 81). CMVD was defined as the absence of coronary artery stenosis and epicardial spasms, the presence of inverted lactic acid levels between the intracoronary and coronary sinuses, or an adenosine triphosphate-induced coronary flow reserve ratio < 2.5. CYP2C19 PMs have two loss-of-function (LOF) alleles (*2, *3). Extensive metabolizers have no LOF alleles, and intermediate metabolizers have one LOF allele. The ratio of CYP2C19 PM and hs-CRP levels in CMVD was significantly higher than that of controls, especially in women (40.9 vs. 13.8%, P = 0.013; 0.11 ± 0.06 vs. 0.07 ± 0.04 mg/dl, P = 0.001). Moreover, in each CYP2C19 genotype, hs-CRP levels in CMVD in CYP2C19 PMs were significantly higher than those of the controls, especially in women (0.15 ± 0.06 vs. 0.07 ± 0.03, P = 0.004). Multivariate analysis for CMVD indicated that the female sex, current smoking, and hypertension were predictive factors, and that high levels of hs-CRP and CYP2C19 PM were predictive factors in women only (odds ratio 3.5, 95% confidence interval 1.26-9.93, P = 0.033; odds ratio 4.1, 95% confidence interval 1.15-14.1, P = 0.038). CYP2C19 PM genotype may be a new candidate risk factor for CMVD via inflammation exclusively in the female population.

Association of CYP2C19 variants and epoxyeicosatrienoic acids on patients with microvascular angina.

Categorization as a cytochrome P450 (CYP) 2C19 poor metabolizer (PM) is reported to be an independent risk factor for cardiovascular disease. Epoxyeicosatrienoic acids (EETs) are metabolites of arachidonic acid by CYP2C19 epoxygenases and anti-inflammatory properties, especially in microvascular tissues. We examined the association of CYP2C19 polymorphisms and EETs on microvascular angina (MVA) caused by coronary microvascular dysfunction. We examined CYP2C19 genotypes in patients with MVA (n = 71) and healthy subjects as control (n = 71). MVA was defined as the absence of coronary artery stenosis and epicardial spasms and the presence of inversion of lactic acid levels between intracoronary and coronary sinuses in acetylcholine-provocation test or the adenosine-triphosphate-induced coronary flow reserve ratio was below 2.5. CYP2C19 PM have two loss-of-functon alleles (*2, *3). We measured serum dihydroxyeicosatrienoic acid (DHET) as representative EET metabolite. MVA group showed significantly higher CYP2C19 PM incidence (35% vs. 16%; P = 0.007) and high sense C-reactive protein (hs-CRP) levels (0.127 ± 0.142 vs. 0.086 ± 0.097 mg/dl; P = 0.043) than those of controls. Moreover, in MVA group, hs-CRP levels in CYP2C19 PM were significantly higher than that of non-PM (0.180 ± 0.107 vs. 0.106 ± 0.149 mg/dl, P = 0.045). Multivariate analysis indicated that smoking, hypertension, high hs-CRP, and CYP2C19 PM are predictive factors for MVA. In MVA group, DHET levels for CYP2C19 PM were significantly lower than that of non-PM [10.9 ± 1.64 vs. 14.2 ± 5.39 ng/ml, P = 0.019 (11,12-DHET); 15.2 ± 4.39 vs. 17.9 ± 4.73 ng/ml, P = 0.025 (14,15-DHET)]. CYP2C19 variants are associated with MVA. The decline of EET-based defensive mechanisms owing to CYP2C19 variants may affect coronary microvascular dysfunction.

Differential impact of peripheral endothelial dysfunction on subsequent cardiovascular events following percutaneous coronary intervention between chronic kidney disease (CKD) and non-CKD patients.

Chronic kidney disease (CKD) status might modify the predictive effect of peripheral endothelial dysfunction on cardiovascular events after percutaneous coronary intervention (PCI). The aim of this study was to examine the differential effect of peripheral endothelial dysfunction on clinical outcome after PCI between CKD and non-CKD patients. We conducted a cohort study of 435 patients following PCI. CKD was defined as estimated glomerular filtration rate <60 mL/min/1.73 m(2). Peripheral endothelial dysfunction was examined using reactive hyperemia-peripheral arterial tonometry index (RHI), and we divided patients into low- and high-natural logarithmic RHI (Ln-RHI) group. The endpoint was a composite of cardiovascular death, nonfatal myocardial infarction, ischemic stroke, hospitalization due to unstable angina pectoris, and coronary revascularization. A total of 56 patients had a cardiovascular event. Patients who suffered a cardiovascular event had significantly lower Ln-RHI than other patients in the non-CKD group (0.46 ± 0.18 versus 0.60 ± 0.25; P = 0.002). Kaplan-Meier analysis demonstrated a significantly higher probability of cardiovascular events in low Ln-RHI patients in the non-CKD group (log-rank test: P = 0.003). Multivariate Cox proportional hazards analysis identified Ln-RHI as an independent and significant predictor of future cardiovascular events in the non-CKD group (HR: 0.096; 95 % CI 0.02-0.47; P = 0.004) but not in the CKD group. There was a differential effect of peripheral endothelial dysfunction on clinical outcome after PCI between CKD and non-CKD patients, and peripheral endothelial dysfunction significantly correlates with subsequent cardiovascular events after PCI in non-CKD patients.

Clinical characteristics and intravascular ultrasound findings of culprit lesions in elderly patients with acute coronary syndrome.

Acute coronary syndrome (ACS) is one of the main causes of cardiovascular death. According to rapid aging of society, the peak age of ACS onset has grown older globally. Despite growing recognition of the necessity to build the ACS prevention strategy in the elderly, patients background and culprit lesion morphology of these elderly ACS patients have not been well studied. We sought to assess the clinical characteristics and intravascular ultrasound (IVUS) findings of the culprit lesions in elderly ACS patients. One-hundred and fifty-eight consecutive ACS patients whose culprit lesions imaged by pre-intervention IVUS were divided into two groups based on the age of onset: elderly [E] group (≥75 years, n = 65) and non-elderly [NE] group (<75 years, n = 93). As compared with NE group, hemoglobin (12.7 ± 2.0 g/dL vs. 13.7 ± 1.6 g/dL, p = 0.001), estimated glomerular filtration rate (62.5 ± 22.5 mL/min/1.73 m(2) vs. 75.5 ± 20.5 mL/min/1.73 m(2), p = 0.0001), and body mass index (22.9 ± 3.4 kg/m(2) vs. 24.5 ± 3.4 kg/m(2), p = 0.003) were significantly lower, and comorbid malignancy was more common (20.0 vs 6.5 %, p = 0.01) in E group. Although whole culprit segment was not positively remodeled (mean vessel area was 15.2 ± 5.6 mm(3)/mm vs. 16.2 ± 5.1 mm(3)/mm, p = 0.16) in E group, at maximum external elastic membrane site of the culprit lesion, lumen area was smaller (5.5 ± 3.2 mm(2) vs. 6.7 ± 3.5 mm(2), p = 0.04), and plaque burden tended to be more abundant (70 ± 13 vs. 66 ± 13 %, p = 0.08). Interestingly, echo attenuation arc of culprit attenuated plaque was significantly greater in E group than in NE group (157 ± 83° vs. 118 ± 60°, p = 0.01). In conclusion, extracardiac comorbidity was more common in elderly ACS patients, and their culprit coronary lesions were still rupture prone, and "vulnerable."

Single-wire pressure and flow velocity measurement for quantifying microvascular dysfunction in patients with coronary vasospastic angina.

Endothelial and vascular smooth muscle dysfunction of epicardial coronary arteries play a pivotal role in the pathogenesis of vasospastic angina (VSA). However, coronary microvascular (MV) function in patients with VSA is not fully understood. In the present study, subjects without coronary obstruction were divided into two groups according to the acetylcholine provocation test: VSA group (n = 29) and non-VSA group (n = 21). Hyperemic MV resistance (hMR) was measured using a dual-sensor (Doppler velocity and pressure)-equipped guidewire, and guidewire-derived hemodynamic parameters were compared. There were no between-group differences in clinical demographics, including potential factors affecting MV function (e.g., diabetes). Although coronary flow velocity reserve was similar between the two groups [2.4 ± 1.0 (VSA group) vs. 2.4 ± 0.9 (non-VSA group); P = 0.8], coronary vessel resistance and hMR were significantly elevated in the VSA group compared with the non-VSA group (2.6 ± 3.1 vs. 1.2 ± 0.8, P = 0.04; 1.9 ± 0.6 vs. 1.6 ± 0.5, P = 0.03, respectively). Coronary vasospasm, older age, E/e', and estimated glomerular filtration rate were significantly associated with MV dysfunction [defined as ≥ median value of hMR (1.6)] in univariate analysis. Coronary vasospasm most strongly predicted higher hMR in multivariate logistic regression analysis (odds ratio, 4.61; 95% confidence interval, 0.98-21.60; P = 0.053). In conclusion, coronary MV resistance is impaired in patients with VSA compared with non-VSA patients, whereas coronary flow velocity reserve is maintained at normal levels in both groups. In vivo assessment of hMR might be a promising index of coronary MV dysfunction in patients with VSA.

Gender differences in impact of CYP2C19 polymorphism on development of coronary artery disease.

The aim was to clarify whether CYP2C19 polymorphism is associated with the development of coronary artery disease (CAD). This study enrolled 723 patients with CAD (men 71%, 70 years) and healthy subjects undergoing a medical checkup (n = 453) as controls (men 69%, 53 years). We analyzed the incidence of CYP2C19 polymorphism and its association with the development of CAD in the absence of diabetes, dyslipidemia, and chronic kidney disease to minimize the influence of conventional coronary risk factors. In the analysis without risk factors, there was no difference in the incidence of the CYP2C19 genotype between CAD (n = 115) and control (n = 194) groups [extensive metabolizer, intermediate metabolizer, poor metabolizer (PM) in non-risk CAD: 33%, 46%, 21%, respectively; in non-risk control: 31%, 52%, 17%, respectively]. Analysis between CAD and control groups by the χ test showed that there was significant difference in distribution of CYP2C19 genotype in women alone (P = 0.025) but not in total subjects (P = 0.471) or men (P = 0.678), respectively. CYP2C19 PM was an independent predictor of CAD risk in women alone (odds ratio, 10.717; 95% confidence interval, 1.753-65.505; P = 0.010) but not in men. CYP2C19 PM status might be associated with the development of CAD as a disease susceptibility gene, especially in women.

High mortality rate in hemodialysis patients who undergo invasive cardiovascular procedures related to peripheral artery disease - community-based observational study in Kumamoto Prefecture - .

BACKGROUND: Cardiovascular disease is a major cause of mortality in hemodialysis patients. The aim was to assess the relationship of various invasive cardiovascular procedures (ICP) to clinical outcome in hemodialysis patients. METHODS AND RESULTS: A total of 5,813 patients at 76 facilities were on maintenance hemodialysis in Kumamoto Prefecture. Of these, 4,807 patients at 58 institutions were enrolled. Of 4,807 patients, 212 ICP (4.4%) were performed for various cardiovascular diseases in 189 patients (3.9%). ICP included PCI (n=80), endovascular treatment (n=59), radiofrequency catheter ablation (n=8), implantation of permanent pacemaker (n=15) and ICD (n=5), thoracotomy for valvular diseases (n=16), CABG (n=14), bypass surgery for peripheral artery disease (PAD; n=8), and artificial vessel replacement for aneurysm or aortic dissection (n=7). The overall mortality rate was 10.1% (19/189 patients). The mortality rate was highest in patients who underwent ICP for PAD, compared with other ICP (PAD, 18.2%; non-PAD, 6.7%, P=0.017). Infection and PAD were significant predictors of mortality (infection: OR, 8.30; 95% CI: 1.29-65.13, P=0.027; PAD: OR, 3.76; 95% CI: 1.35-10.48, P=0.012). The presence of inflammation/malnutrition factors was associated with high mortality (OR, 15.49; 95% CI: 3.22-74.12, P=0.0006). CONCLUSIONS: In this community-based registry study of 4,807 hemodialysis patients, the mortality rate of PAD patients was high despite ICP.

Differential Effects of Strong and Regular Statins on the Clinical Outcome of Patients With Chronic Kidney Disease Following Coronary Stent Implantation　- The Kumamoto Intervention Conference Study (KICS) Registry.

BACKGROUND: The aim of this study was to examine the effects of different statins on the clinical outcomes of Japanese patients with coronary stent implants. METHODS AND RESULTS: This study included 5,801 consecutive patients (males, 4,160; age, 69.7±11.1 years, mean±SD) who underwent stent implantation between April 2008 and March 2011. They were treated with a strong statin (n=3,042, 52%, atorvastatin, pitavastatin, or rosuvastatin), a regular statin (n=1,082, 19%, pravastatin, simvastatin, or fluvastatin) or no statin (n=1,677, 29%). The patients with chronic kidney disease (CKD) were divided into mild-to-moderate CKD (30≤eGFR<60, n=1,956) and severe CKD (eGFR <30, n=559). Primary endpoints included cardiovascular death and nonfatal myocardial infarction, including stent thrombosis and ischemic stroke. The clinical outcome for the primary endpoint in mild-to-moderate CKD patients treated with a strong statin (hazard ratio 0.50, 95% confidence interval 0.31-0.81; P=0.005) was significantly lower than in those on no statins, but that in the patients treated with a regular statin was not (P=0.160). The clinical outcome for the primary endpoint in severe CKD patients treated with a strong or regular statin was no different than not being on statin therapy (P=0.446, P=0.194, respectively). CONCLUSIONS: In patients with mild-to-moderate CKD, only strong statins were associated with lower risk compared with no statin, but regular statins were not. It is possible that taking a strong statin from the early stage of CKD is useful for suppression of cardiovascular events.

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.

Validation of the high mortality rate of Malnutrition-Inflammation-Atherosclerosis syndrome: -Community-based observational study.

BACKGROUND: Malnutrition-Inflammation-Atherosclerosis (MIA) factors significantly and independently affect life prognosis of hemodialysis (HD) patients. We re-evaluated Japanese data, which have progressed ahead from a community-based observational study. The present study was designed to assess the contribution of these MIA factors to the mortality rate of Japanese HD patients in a community of 1.8 million people over a 36-month follow-up period. METHODS AND RESULTS: A total of 5813 patients at 76 facilities were on maintenance HD in the Kumamoto Prefecture. Specifically, 4807 of these patients at 58 institutions were enrolled. Patients who exhibited lower serum albumin and higher serum C-reactive protein levels were defined as "malnourished" and "inflamed", respectively, compared with the median values. Patients who underwent invasive procedures for atherosclerotic diseases were defined as "atherosclerotic". The 36-month all-cause mortality rate in Japanese HD patients was 12.4%. This rate directly correlated with the number of MIA factors. The odds ratio of the all-cause mortality rate markedly and significantly increased as the number of factors increased. The presence of 3 MIA factors in HD patients was a significant predictor of mortality, as evidenced by a multivariate logistic regression analysis. CONCLUSIONS: This study clearly demonstrated the close association between MIA syndrome and high mortality in Japanese HD patients. Early detection and the adjustment of MIA factors are mandatory.

Effects of the Mean Amplitude of Glycemic Excursions and Vascular Endothelial Dysfunction on Cardiovascular Events in Nondiabetic Patients With Coronary Artery Disease.

BACKGROUND: Mean amplitude of glycemic excursion (MAGE) is commonly used to gauge the degree of glucose level fluctuations. MAGE plays a significant role in vascular endothelial dysfunction and cardiovascular events in patients with diabetes mellitus (DM), but its significance is not clear in non-DM patients. Thus, we examined the impact of MAGE and vascular endothelial dysfunction on clinical outcomes in non-DM patients with coronary artery disease. METHODS AND RESULTS: We followed non-DM patients (n=65) for 12 months who underwent percutaneous coronary intervention and assessed the relationship among MAGE, reactive hyperemia index (RHI) measured by reactive hyperemia peripheral arterial tonometry as endothelial function, and cardiovascular events. Cardiovascular events analyzed were cardiovascular death, myocardial infarction, unstable angina, and revascularizations. Compared with patients with MAGE <65 mg/dL (normal glycemic excursions), the group with MAGE ≥65 mg/dL (high glycemic excursions) had significantly higher high-sensitivity C-reactive protein (0.10±0.11 mg/dL versus 0.18±0.13 mg/dL, P=0.006) and lower RHI (0.64±0.21 versus 0.51±0.22, P=0.035). The multivariable analysis identified high MAGE and low RHI (≤0.56) as risk factors associated with cardiovascular events (hazard ratio, 5.6; 95% RI, 1.72-18.4 [P=0.004] versus hazard ratio, 4.5; 95% RI, 1.37-14.9 [P=0.013]). When the prognosis was classified by combination with MAGE and RHI, the incidence of cardiovascular events was 46.7% (high MAGE+low RHI), 26.7% (high MAGE+high RHI), 20.0% (low MAGE+low RHI), and 6.6% (low MAGE+high RHI) in descending order (P=0.014). Receiver operating characteristic curve analysis revealed that MAGE, RHI, and MAGE+RHI were each associated with cardiovascular events (area under the curve 0.780, 0.727, and 0.796, respectively). CONCLUSIONS: MAGE was associated with cardiovascular events in non-DM patients with coronary artery disease. Furthermore, the combination with MAGE and RHI was useful for further subdivision of the risk of cardiovascular events.

CYP2C19 variants and epoxyeicosatrienoic acids in patients with microvascular angina.

BACKGROUND: Categorization as a cytochrome P450 (CYP) 2C19 poor metabolizer (PM) is reported to be an independent risk factor for cardiovascular disease. Epoxyeicosatrienoic acids (EETs) are metabolites of arachidonic acid by CYP2C19 epoxygenases and anti-inflammatory properties, especially in microvascular tissues. We examined the impact of CYP2C19 polymorphisms and EETs on the patients with microvascular angina (MVA) caused by coronary microvascular dysfunction. METHODS AND RESULTS: We examined CYP2C19 genotypes in patients with MVA (n = 81). MVA was defined as absence of coronary artery stenosis and epicardial spasms, and the presence of inversion of lactic acid levels between intracoronary and coronary sinuses in acetylcholine-provocation test or the adenosine-triphosphate-induced coronary flow reserve ratio was below 2.5. CYP2C19 PM have two loss-of-functon alleles (*2, *3). We measured serum dihydroxyeicosatrienoic acid (DHET) as representative EET metabolite. In MVA, the patients with CYP2C19 PM were 34.6% and high sense C-reactive protein (hs-CRP) levels in CYP2C19 PM were significantly higher than that of non-PM group (0.165 ± 0.116 vs. 0.097 ± 0.113 mg/dL, P = 0.026). Moreover, DHET levels in CYP2C19 PM were significantly lower than that of non-PM (10.4 ± 4.58 vs. 15.6 ± 11.1 ng/mL, P = 0.003 (11,12-DHET); 12.1 ± 3.79 vs. 17.3 ± 6.49 ng/mL, P = 0.019 (14,15-DHET)). CONCLUSIONS: The decline of EET owing to CYP2C19 variants may affects coronary microvascular dysfunction via chronic inflammation.

Clinical outcomes of percutaneous coronary intervention for acute coronary syndrome between hospitals with and without onsite cardiac surgery backup.

BACKGROUND: Based on the 2011 American College of Cardiology/American Heart Association percutaneous coronary intervention (PCI) guideline, it is recommended that PCI should be performed at hospital with onsite cardiac surgery. But, data suggest that there is no significant difference in clinical outcomes following primary or elective PCI between the two groups. We examined the impact of with or without onsite cardiac surgery on clinical outcomes following PCI for acute coronary syndrome (ACS). METHODS AND RESULTS: From August 2008 to March 2011, subjects (n=3241) were enrolled from the Kumamoto Intervention Conference Study (KICS). Patients were assigned to two groups treated in hospitals with (n=2764) or without (n=477) onsite cardiac surgery. Clinical events were followed up for 12 months. Primary endpoint was in-hospital death, cardiovascular death, myocardial infarction, and stroke. And we monitored in-hospital events, non-cardiovascular deaths, bleeding complications, revascularizations, and emergent coronary artery bypass grafting (CABG). There was no overall significant difference in primary endpoint between hospitals with and without onsite cardiac surgery [ACS, 7.6% vs. 8.0%, p=0.737; ST-segment elevation myocardial infarction (STEMI), 10.4% vs. 7.5%, p=0.200]. There was also no significant difference when events in primary endpoint were considered separately. In other events, revascularization was more frequently seen in hospitals with onsite surgery (ACS, 20.0% vs. 13.0%, p<0.001; STEMI, 21.9% vs. 14.5%, p=0.009). We performed propensity score matching analysis to correct for the disparate patient numbers between the two groups, and there was also no significant difference for primary endpoint (ACS, 8.6% vs. 7.5%, p=0.547; STEMI, 11.2% vs. 7.5%, p=0.210). CONCLUSIONS: There is no significant difference in clinical outcomes following PCI for ACS between hospitals with and without onsite cardiac surgery backup in Japan.

The dawn of a new era in onco-cardiology: The Kumamoto Classification.

The term "onco-cardiology" has been used in reference to cardiotoxicity in the treatment of malignant disease. In actual clinical situations, however, cardiovascular disease (CVD) associated with malignant disease and the concurrence of atherosclerotic disease with malignant disease are commonly observed, complicating the course of treatment. Patients with malignant disease associated with coronary artery disease often die from the cardiovascular disease, so it is essential to classify these disease states. Additionally, the prevalence of these classifications makes it easy to manage patients with malignant disease and coronary artery disease. We divided the broad field of onco-cardiology into 4 classifications based on clinical scenarios (CSs): CS1 represents the so-called paraneoplastic syndrome. CS2 represents cardiotoxicity during treatment of malignant diseases. CS3 represents the concurrence of atherosclerotic disease with malignant disease, and CS4 represents cardiovascular disease with benign tumors. This classification facilitates the management of patients with malignant disease and coronary artery disease by promoting not only the primary but also the secondary prevention of CVD.

Unprotected left main intervention for surgery-ineligible patients with coronary artery disease-Usefulness of micro-CT images for stent.

BACKGROUND: Percutaneous coronary intervention (PCI) for unprotected left main truncus (LMT) lesions is controversial. Inoperable status with advanced age, renal dysfunction, frailty, or patient request may require an unprotected left main PCI. PCI for LMT is not recommended in the typical clinical situation; however, when it is the only feasible option, the performance is not bad. We demonstrated the result of a cobalt-chromium everolimus-eluting stent (CoCr-EES) in the LMT stenting and serial changes via micro-computed tomography (µCT). µCT is an established imaging technique used for high-resolution, non-destructive assessment of vascular samples. The technique has drawn increasing interest for investigations of atherosclerotic arteries in both humans and animal models. There are no reports regarding the linkage between clinical results and µCT images. METHODS AND RESULTS: Between January 2009 and December 2014, we recruited 118 consecutive, unprotected LMT stenting cases in our institution. We examined the clinical outcomes and angiographic results with a CoCr-EES compared with a first-generation drug-eluting stent. The primary endpoint of this registry was the rate of one-year major adverse cardiac events (MACE). The one-year MACE rate was 2.54%; this did not include the CoCr-EES. We established LMT bifurcation models (mini-crush and culotte) using a CoCr-EES and obtained µCT images of the CoCr-EES. The images showed no deformation or strut apposition. CONCLUSION: CoCr-EES performed well in LMT in our institution and according to µCT. µCT images may be useful for anatomical simulation in stent deployment.

The real-world prevalence of cardiovascular events related to coronary spasm after percutaneous coronary intervention.

BACKGROUND: It is unknown to what extent coronary spasm affects cardiovascular events after percutaneous coronary intervention (PCI) in clinical practice. The aim was to examine the prevalence of cardiovascular events related to coronary spasm following PCI according to stent type. METHODS: We enrolled 933 consecutive patients treated with coronary stent implantation, including bare metal stents (BMS; n=238), first-generation drug-eluting stents (1st DES; n=185), and second-generation DES (2nd DES; n=510). We compared stent-oriented endpoints (SOEs; stent thrombosis, target vessel myocardial infarction or unstable angina, target lesion revascularization, and cardiac death) and the differences in SOE related to coronary spasm across stent types. Among the SOEs, spasm-related cardiac event was defined based on JCS guideline. RESULTS: The prevalence of SOE for each stent type was 16.8% (BMS), 16.8% (1st DES), and 7.8% (2nd DES) (p<0.001) and the rates of cardiovascular events related to coronary spasm were 2.9%, 3.2%, and 0.4%, respectively (p=0.005). Multivariate analysis identified the non-use of statin (HR, 0.275, 95% CI, 0.087-0.871, p=0.028) and non-use of 2nd DES (hazard ratio, 0.196, 95% confidence interval, 0.043-0.887, p=0.034) as independent predictors of cardiac events related to coronary spasm. CONCLUSION: The prevalence of cardiovascular events related to coronary spasm was the lowest in patients with 2nd DES. The 2nd DES may be more efficacious and safer from the point of view of the reduction of cardiac events due to coronary spasm during statin therapy.

Clinical and morphological presentations of acute coronary syndrome without coronary plaque rupture - An intravascular ultrasound study.

BACKGROUND: Although acute coronary syndrome (ACS) mainly arises from plaque ruptures (PR), precise mechanisms underlying ACS without PR are unknown. We sought to examine clinical, angiographic and intravascular ultrasound (IVUS) characteristics of ACS without PR. METHODS AND RESULTS: Culprit lesions of 161 ACS patients were categorized by the presence or absence of PR (PR group: n=57, Non-PR group: n=104). Lower abdominal circumference (86±10cm vs 90±9cm, p=0.02), lower prevalence of myocardial infarction (53% vs 82%, p=0.0002), and higher prevalence of definite vasospasm (15% vs 2%, p=0.006) were found in Non-PR group. Morphologically, Non-PR group was associated with simpler Ambrose classification (36% vs 14%, p=0.004), less hypoechoic plaque (45% vs 65%, p=0.04) and lower incidence of IVUS-detected thrombus (21% vs 54%, p<0.0001), compared with PR group. On quantitative IVUS, although minimum lumen area (MLA) was similar between the groups, vessel (14.2±5.4mm(2) vs 17.5±5.1mm(2), p=0.0002) and plaque (11.6±5.0mm(2) vs 14.9±4.9mm(2), p<0.0001) areas were significantly smaller at MLA site in Non-PR group than in PR group. On multivariate analysis, average plaque area was only an independent IVUS-predictor of non-rupture ACS (odds ratio: 0.85, p=0.01). CONCLUSION: Compared to ACS with PR, non-rupture ACS arise from more hyperechoic (allegedly "stable") plaque with smaller vessel and plaque area, leading to lower incidence of thrombotic occlusion. Coronary vasospasm might be a possible pathogenic mechanism underlying non-rupture ACS.

Prevalence of coronary macro- and micro-vascular dysfunctions after drug-eluting stent implantation without in-stent restenosis.

BACKGROUND: The aim was to examine the prevalence and characteristics of epicardial vasomotor abnormality (EVA) and coronary microvascular dysfunction (CMD) including endothelium-dependent (EDCMD) or -independent (EICMD) in patients following a second-generation drug-eluting stent (second DES) implantation without in-stent restenosis. METHODS AND RESULTS: In 105 patients who underwent second DES implantation in the left anterior descending coronary artery (74 men; mean age, 67.9±9.6years), and in 105 suspected angina patients without stenting (65 men; mean age 66.4±9.1years), we evaluated EVA using the acetylcholine provocation test, EDCMD and EICMD by measuring the coronary flow reserve and the relationship between myocardial ischemia (intracoronary lactate production between aorta and coronary sinus and ST-T changes) or recurrent angina and vascular function. There was no difference in the incidence of EVA between DES and control (49.5% versus 55.2%; P=0.41). Given that the prevalence of CMD was higher in DES than in control (59.0% versus 29.5%; P<0.001), CMD may be associated with stent placement. Of the CMD patients, EDCMD alone, EICMD alone, and both CMDs were found in 40.3%, 22.6%, and 37.1%, respectively. Myocardial ischemia was detected in 42.4% of patients, and recurrent angina was more common in the presence of both EDCMD and EICMD in patients with EVA or CMD compared to patients with normal vascular function (EVA, 42.9% versus 7.7%, P=0.015: CMD, 39.1% versus 7.7%, P=0.007). CONCLUSIONS: Myocardial ischemia and recurrent angina may be caused by the presence of both EDCMD and EICMD after a second DES implantation without ISR.

Impact of Statin Therapy on Clinical Outcome in Patients With Coronary Spasm.

BACKGROUND: Statin therapy reduces the risk of cardiovascular events in patients with obstructive coronary artery disease. The aim of the present study was to determine the effects of statins on the prognosis of patients with coronary vasospastic angina (VSA) free of significant atherosclerotic stenosis. METHODS AND RESULTS: After exclusion of 475 from 1877 consecutive patients who underwent an acetylcholine-provocation test between January 1991 and December 2010, data of 640 VSA patients without significant organic stenosis of the remaining 1402 were analyzed retrospectively. Propensity score matching was performed to reduce the effect of treatment-selection bias and possible confounders. The primary endpoint was major adverse cardiac events (MACE), including cardiac death, nonfatal myocardial infarction, and unstable angina. Among the study population, dyslipidemia on admission was identified in 160 of 168 (95.2%) patients of the statin group compared with only 125 of 472 (26.5%) of the no-statin group. Of the 640 patients, 24 (3.8%) developed MACE. Multivariate Cox hazard regression analysis identified statin therapy as a significant negative predictor of MACE (hazard ratio, 0.11; 95% CI, 0.02-0.84; P=0.033). In the propensity-score matched cohorts (n=128 each), Kaplan-Meier survival curve showed a better 5-year MACE-free survival rate for patients of the statin group compared to the no-statin group (100% vs 91.7%, respectively; P=0.002). CONCLUSIONS: Statin therapy correlated with a lower rate of cardiovascular events in VSA patients free of significant organic stenosis. Statins seems to improve the prognosis of VSA patients free of significant organic stenosis.

Distribution of Ankle-Brachial Index among Inpatients with Cardiovascular Disease: Analysis Using the Kumamoto University Hospital Medical Database.

OBJECTIVE: To describe the distribution of ankle-brachial index (ABI) among Japanese cardiovascular inpatients and to explore risk factors of peripheral arterial disease (PAD) associated with ABI ≤0.9. MATERIALS AND METHODS: This study was a retrospective analysis using clinical record databases of patients with cardiovascular disease admitted to the Department of Cardiovascular Medicine, Kumamoto University Hospital between 2007 and 2014. RESULTS: Of 3639 patients included in the analysis, male patients accounted for 62.1% and the mean age of patients was 66.1 years. Ischemic heart disease (IHD) was observed in 49.1%. ABI ≤0.9 was observed in 11.3% of all patients, 14.1% in the IHD group and 8.5% in the non-IHD group. Age of ≥65 years (odds ratio [OR]: 2.93, 95% confidence interval [CI]: 2.22-3.86), current smoking (OR: 2.28, 95%CI:1.71-3.04), diabetes (OR: 2.15, 95%CI:1.71-2.71), hypertension (OR: 1.42, 95%CI:1.12-1.81) and chronic kidney disease (OR: 2.52, 95%CI:1.82-3.48) were significantly associated factors with ABI ≤0.9. CONCLUSIONS: This study suggests that PAD is prevalent even in patients without IHD. Active management of risk factors, early detection of PAD based on ABI, and therapeutic intervention could be effective in preventing future cardiovascular events or death.