Recent studies have suggested that omeprazole may reduce the inhibitory effect of clopidogrel on platelet aggregation. The United States Food and Drug Administration (FDA) has issued an update regarding this drug-drug interaction.
This study aimed to evaluate the changing prescription pattern of omeprazole in patients taking clopidogrel after the FDA update regarding the clopidogrel-omeprazole interaction.
A pharmacy database system was used to identify all prescriptions of clopidogrel alone, clopidogrel and omeprazole, or clopidogrel and ranitidine from May 1, 2009 until May 31, 2010.
A total of 2,899 prescriptions were entered into the final data analysis. There was a statistically significant drop in omeprazole prescription with clopidogrel from 46.6% in the period before the FDA update to 38.2% after the update (P = 0.0037). In addition, a signifi cant increase was observed in the ranitidine prescription from 9.7% to 20.1% during the same time frame (P = 0.0059) without any significant change between the two study periods for those on clopidogrel alone without any protective gastrointestinal bleeding drug (43% versus 41.7%). On the other hand, of the 732 patients who were on clopidogrel and omeprazole during the period before the FDA update, 396 patients (54.1%) were taken off omeprazole, 274 (37.4%) were kept on both drugs, 59 (8.1%) had their omeprazole switched to ranitidine after the FDA update, and 3 patients were lost to follow-up (0.4%).
The present findings indicate a significant change in prescription pattern for omeprazole after the FDA update by taking patients off omeprazole or to a lesser extent replacing it with ranitidine.

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Vaccines are commonly used as a preventive medicine for infectious diseases worldwide, however, clinical trials on an amyloid beta vaccine for Alzheimer’s disease represents a new concept in the field of vaccinations. Several recent studies indicate the potential of therapeutic vaccines as well as classical vaccines as preventive medicines. A number of therapeutic vaccines for cancer have been developed as novel immunotherapies. Their targets are usually specifi c antigens in cancer cells, allowing activated cytotoxic T cells (CTLs) to attach and remove the antigen-presenting cancer cells. Recently, we and others have attempted to develop a therapeutic vaccine against hypertension. The vaccine target is angiotensin II (AngII), and induced anti-AngII antibodies could efficiently ameliorate high blood pressure. However, because AngII is an endogenous hormone, we must avoid the induction of autoimmune diseases by administration of an AngII vaccine. Therefore, our system was used to design a therapeutic vaccine that elicits anti-AngII antibodies without CTL activation against AngII. Because the target antigen itself does not include T cell epitopes, the immunogenic molecule (ie, KLH) provides antigen that supports the activation of T cells. In particular, helper T cells may activate B cells that produce antibodies against our specific antigen. In this review, we will explain our concept of therapeutic vaccines based on our recent data.

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Inflammasomes are multiple protein complexes that serve as molecular platforms to activate caspase-1 and regulate maturation of a potent proinfl ammatory cytokine, interleukin (IL)-1β, as well as proinfl ammatory cell death, pyroptosis. Although several types of inflammasomes have been reported so far, recent investigations indicate that the NLRP3 inflammasome recognizes non-microbial danger signals and leads to sterile inflammatory responses in various disease conditions. Sterile inflammatory responses are also implicated in the development of myocardial infarction (MI). In particular, IL-1β is an early and prominent mediator of inflammatory responses in MI, suggesting the pathophysiologic role of NLRP3 inflammasomes in MI. This review highlights the current state of knowledge regarding the role of NLRP3 inflammasomes in MI.

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The effects of statins on the prognosis of patients with left ventricular (LV) systolic dysfunction remain controversial. The aim of this study was to assess the effect of statin treatment on clinical outcomes in acute myocardial infarction (AMI) patients with LV systolic dysfunction. A total of 5,119 AMI patients with LV ejection fraction less than 50% on the initial echocardiogram were analyzed in the Korean Acute Myocardial Infarction Registry. The study population was divided into 4 groups according to the level of high sensitivity C-reactive protein (hs-CRP) and statin treatment: low hs-CRP (hs-CRP ≤ 2.0 mg/L) and high hs-CRP (hs-CRP > 2 mg/L) with or without statin therapy. We evaluated the incidence of major adverse cardiac events (MACEs) including cardiac death, reinfarction, target lesion revascularization, and coronary artery bypass grafting during a 12-month period in each group. Statin therapy did not signifi cantly prevent the MACEs in the low hs-CRP groups (with statin: 10.1% versus without statin: 12.0%, P = 0.249). In the high hs-CRP groups, however, the incidence of MACEs was significantly decreased with statin treatment (with statin: 11.3%, without statin: 20.8%, P < 0.001). These findings were consistently observed in all subgroups of the high-hs CRP group, including the subgroup with an LV ejection fraction less than 40%. In a multivariable logistic regression analysis of the high hs-CRP group, lack of statin therapy was a significant predictor of MACE incidence (odds ratio: 1.573, 95% confi dence interval: 1.079-2.293, P = 0.018). The statin treatment was associated with better outcome in AMI and LV dysfunction patients with hs-CRP ≥ 2 mg/dL.

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The aim of this study was to determine the diagnostic accuracy of early/delayed ¹²³I-β-methyl-iodophenyl pentadecanoic acid (¹²³I-BMIPP) planar images to detect disrupted fatty acid metabolism in patients with vasospastic angina (VSA). Heart-to-mediastinum (H/M) ratios and washout rates were calculated from early and late (15 minutes and 4 hours after tracer injection, respectively) planar ¹²³I-BMIPP images from 13 hypertensive control individuals (mean age, 69.5 years) and 37 patients with VSA (mean age, 62.8 years) 10.5 (mean) days after administering the intracoronary acetylcholine provocation test. Patients with VSA had significantly lower early H/M and delayed H/M ratios (early; 2.2 ± 0.3 versus 2.7 ± 0.5, P = 0.007; delayed: 1.8 ± 0.3 versus 2.4 ± 0.4, P < 0.001) and significantly greater washout rates (39.8 ± 11.8% versus 29.3 ± 11.7%, P = 0.011) than controls. The overall area under the curve defi ning the accuracy of diagnostic performance was 0.76 (95% confidence interval (CI): 0.59-0.92) and 0.85 (95% CI, 0.73-0.98) for the early and delayed H/M ratios and 0.74 (95% CI, 0.73-0.90) for washout rates. Planar ¹²³I-BMIPP imaging can diagnose coronary artery spasm with acceptable diagnostic performance and indicates that the delayed H/M ratio has a powerful ability to assess recent ischemia. This technique might be useful in the face of apparently normal coronary angiographic fi ndings during the subacute and chronic phases after ischemic events.

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It remains unclear if the CHADS₂ score or CHA₂DS₂-VASc score is more useful for the risk stratification of ischemic stroke/systemic thromboembolism in Japanese patients with non-valvular paroxysmal atrial fibrillation (NVPAF).
We retrospectively investigated the incidence of ischemic stroke on the basis of CHADS₂ and CHA₂DS₂-VASc scores in 332 NVPAF patients (224 men, mean age, 65 ± 13 years) who were not administered anticoagulation therapy before publication of the 2008 JCS guideline (mean follow-up period, 53 ± 35 months). Annual rates of ischemic stroke/ systemic thromboembolism underlying antiarrhythmic drug therapy were 0.2%/year for the 0-point group; 0.9%/year for the 1-point group; 2.8%/year for the 2-point group; 9.4 %/year for the 3-point group; and 10.9%/year for the ≥ 4-point group on the basis of the CHADS₂ scores, and 0%/year for the 0-point group; 0.6%/year for the 1-point group; 1.0%/ year for the 2-point group; 2.0 %/year for the 3-point group; 5.5%/year for the 4-point group; 9.1%/year for the 5-point group; and 13.7%/year for the ≥ 6-point group on the basis of the CHA₂DS₂-VASc scores. Both higher CHADS₂ and CHA₂DS₂-VASc scores were associated with greater annual rates of ischemic stroke/systemic thromboembolism (P < 0.001). In multivariate logistic regression analysis, the CHADS₂ (odds ratio [OR]:4.74, 95% confidence interval [CI]:2.80-8.00, P < 0.001) and CHA₂DS₂-VASc scores (OR: 4.15, 95% CI:2.57-6.71, P < 0.001) were signifi cant independent predictors for ischemic stroke/systemic thromboembolism. Area under the receiver-operator characteristic curves for predicting ischemic stroke/systemic thromboembolism were 0.89 in the CHA₂DS₂-VASc scores (P < 0.001) and 0.87 in the CHADS₂ scores (P < 0.001).
In Japanese patients with NVPAF, both the CHADS₂ and CHA₂DS₂-VASc scores are useful parameters for the risk stratification of ischemic stroke/systemic thromboembolism.

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It has been demonstrated that a prolonged PR interval is associated with an increased risk of AF. However, the impact of a prolonged PR interval on recurrence of paroxysmal atrial fibrillation (AF) after catheter ablation is not clear. A total of 112 patients with a prolonged PR interval (PR > 200 ms) (PPR group) and 112 age- and gender-matched control patients (on a 1:1 basis) with a normal PR interval (NPR group) were included in this study. AF recurrence was defi ned as the occurrence of confirmed atrial tachyarrhythmia lasting more than 30 seconds beyond 3 months after catheter ablation in the absence of any antiarrhythmic treatment. During a mean follow-up period of 10.9 ± 5.5 months (range, 3–18 months), 61 patients (27.2%) developed recurrence of AF. The recurrence rate was higher in the PPR group than in the NPR group (33.9% versus 20.5%, respectively; P = 0.018). Cox regression analysis with adjustment for age, body mass index, valvular heart disease, left atrial diameter, and pulmonary vein isolation identified only a prolonged PR interval as an independent predictor of recurrence of AF (hazard ratio, 1.81; 95% confidence interval, 1.07–3.05; P = 0.027). Patients with a prolonged PR interval were at an increased risk of AF recurrence after catheter ablation.

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Several studies have demonstrated that tolvaptan (TLV) can improve hyponatremia in advanced heart failure (HF) patients with rare chance of hypernatremia. However, changes in serum sodium concentrations (S-Na) in patients with or without hyponatremia during TLV treatment have not been analyzed.
Ninety-seven in-hospital patients with decompensated HF who had received TLV at 3.75-15 mg/day for 1 week were enrolled. Among 68 “responders”, who had achieved any increases in urine volume (UV) during the fi rst day, urinary sodium excretion during 24 hours (U-NaEx₂₄) increased significantly during one week of TLV treatment along with higher baseline S-Na (P < 0.05 and r = 0.325). Considering a cut-off value (S-Na, 132 mEq/L; AUC, 0.711) for any increases in U-NaEx₂₄, we defi ned “hyponatremia” as S-Na < 132 mEq/L. In hyponatremic responders (n = 25), S-Na increased significantly, although 1 week was not sufficient for normalization (125.8 ± 5.0 versus 128.9 ± 4.3 mEq/L, P < 0.05), along with unchanged U-NaEx₂₄ (2767 ± 2703 versus 2972 ± 2950 mg/day, NS). In contrast, in normonatremic responders (n = 43), S-Na remained unchanged (136.6 ± 3.1 versus 137.4 ± 2.9 mEq/L, NS) along with increased U-NaEx₂₄ (2201 ± 1644 versus 4198 ± 3550 mg/day, P < 0.05).
TLV increased S-Na only in hyponatremic responders by way of pure aquaresis, but increased U-NaEx₂₄ only in normonatremic responders, which explains the scarcity of hypernatremia. Epithelial Na-channels in the distal nephrons, whose repression by TLV increases urinary sodium excretion, may be attenuated by reduced ATP-supply in worse hemodynamics under hyponatremia.

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Previous studies have examined the negative impacts of individual cardiovascular risk (CVR) factors on left atrial (LA)-left ventricular (LV) interaction, whereas the combined effects of these risk factors are insuffi ciently elucidated. We studied 176 asymptomatic patients with CVR factors and age-matched 50 healthy individuals by conventional and 2-dimensional speckle-tracking echocardiography. The patients were classified into 2 groups according to the number of CVR factors: one risk factor (single) group (n = 79) and 2 or more risk factors (comorbid) group (n = 97). The peak early diastolic transmitral flow velocity (E)/peak early diastolic mitral annular motion velocity (e’)/peak systolic LA strain (S-LAs) was used as a surrogate for LA stiffness during ventricular systole. The E/e’/S-LAs was greatest in the comorbid group. The peak systolic LV circumferential and radial strains, peak early diastolic LV radial strain rate, and peak early diastolic LA strain and strain rate were lower in the comorbid group than in the single group. Multivariate regression analysis identifi ed age, body mass index, systolic blood pressure, end-systolic LV diameter, peak systolic mitral annular motion velocity (s’), and peak systolic LV radial strain in the comorbid group, and peak atrial systolic transmitral fl ow velocity and s’ in the single group, as independent predictors of E/e’/S-LAs. Subtle LA and LV dysfunction with individual CVR factors were more aggravated with the comorbid conditions in asymptomatic patients.

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Carotid intima-media thickness (IMT), a measure of atherosclerosis, is modulated by multiple risk factors. Accordingly, comprehensive control of risk factors is indispensable for management of atherosclerosis. In this study, as a posthoc analysis of the JART Study we planned two analyses. In the main analysis, we evaluated the effect of intensive lipidlowering therapy with rosuvastatin on carotid IMT in high-risk patients. We also evaluated efficacy in the presence or absence of each risk factor using the full analysis population in the JART Study. Patients with low-density lipoprotein cholesterol (LDL-C) ≥ 140 mg/dL and max-IMT ≥ 1.1 mm were randomized to rosuvastatin or pravastatin therapy for 12 months. Dosages were allowed to increase to 10 mg/day and 20 mg/day to achieve LDL-goals (aggressive goals for rosuvastatin group and guideline goals for pravastatin group). For the main analysis, we assessed 200 high-risk patients (105 in the rosuvastatin group), as category III or secondary prevention according to the Japan Atherosclerosis Society guideline 2007, whereas we assessed 289 patients in the other analysis. Rosuvastatin significantly slowed the percentage change in mean-IMT at 12 months compared with pravastatin (1.40 ± 10.03% versus 6.43 ± 13.77%, P = 0.005). LDL-C was reduced by 48.1% in the rosuvastatin group and 27.9% in the pravastatin group. The rate of achieving the LDL-C goal was significantly greater in the rosuvastatin group compared with the pravastatin group (P < 0.001). Rosuvastatin slowed the change in mean-IMT in the presence of every risk factor. Thus, intensive lipid-lowering therapy reduced progression of carotid IMT in high-risk patients.

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The aim of this study was to evaluate the correlations between microalbuminuria (MAU) and endothelial function in hypertensive patients with carotid plaques (CP). A total of 71 hypertensive patients with CP (CP group) and 20 healthy people as normal controls (NC group) were enrolled in this study. The CP group was divided into an MAU group (MAU group, n = 33) and a non-microalbuminuria group (NM group, n = 38) according to their urinary albumin excretion rates (UAER). Endothelial function was assessed by flow-mediated dilation (FMD) in the brachial artery by ultrasonography, and nitroglycerin-mediated dilation (NMD) was used as a control test for FMD. Intima-media thickness (IMT) and biochemical parameters were evaluated. The ΔFMD% was significantly lower in patients with and without MAU in the CP group compared to the NC group. All patients with MAU had significantly lower ΔFMD% and ΔNMD% compared to the patients without MAU. ΔFMD% showed significant negative correlations with IMT, systolic blood pressure, glucose, total cholesterol, low density lipoprotein, high-sensitivity C-reactive protein, and log UAER. ΔNMD% demonstrated significant negative correlations with age, IMT, systolic blood pressure, glucose, and log UAER. Stepwise multiple linear regression analysis revealed that FMD was independently correlated with UAER and total cholesterol, while NMD was independently correlated with UAER and age. These results suggest that MAU might aggravate the arterial dysfunction and play a role in the arterial endothelial function in patients with hypertension and CP. Both endothelium-dependent and endothelium-independent vasodilatations were impaired in hypertensive patients with CP.

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An inflammatory response is a key event for endothelial dysfunction. Pentraxin 3 (PTX3) is an infl ammatory protein produced at inflammation sites such as leukocytes and vascular endothelial cells. Here, we compared the relationships between endothelial function assessed by flow-mediated dilation (FMD), and the levels of plasma PTX3 and highsensitive C-reactive protein (hsCRP), another inflammatory protein of the pentraxin family.
Levels of FMD, PTX3 and hsCRP were measured twice within 6 to 8 months and retrospectively analyzed in 36 patients with coronary artery disease. We examined the associations between the values of FMD and the levels of PTX3 and hsCRP at the first measurement, and between the change ratios (second value/first value) of these parameters.
Univariate linear regression analysis showed significantly negative correlations between FMD values and PTX3 and hsCRP levels at the first measurement, and significant associations with taking statins or calcium antagonists. Multivariate linear stepwise regression analysis identified PTX3 levels and taking statins and calcium antagonists as independent factors for endothelial function. The change ratio of FMD correlated more closely with that of PTX3 than of hsCRP (r = -0.446, P = 0.006 versus r = -0.330, P = 0.050). Significantly more patients with decreased FMD values had increased levels of PTX3 than those of hsCRP at the second measurement compared with the fi rst measurement. Furthermore, the ratio of patients with increased PTX3, but not increased hsCRP, was significantly reduced among those with increased, rather than decreased, FMD values.
Endothelial dysfunction might be more accurately predicted by plasma PTX3 levels than by serum hsCRP levels.

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Accumulating evidence suggests that there are direct interactions between β-adrenergic and angiotensin II signaling pathways, and β-blockers protect the heart against angiotensin II-induced cardiac remodeling. Phosphodiesterase 3A (PDE3A) regulates β-adrenergic receptor/protein kinase A signaling by metabolizing cAMP. Therefore, we hypothesized that overexpressed PDE3A has cardioprotective effects against angiotensin II-induced cardiac remodeling by regulating angiotensin II signaling. In the present study, we used transgenic mice with cardiac-specific overexpressed PDE3A1. We showed that continuous administration of angiotensin II caused cardiac hypertrophy in the wild-type mouse heart, but not in the transgenic mouse heart. Angiotensin II induced cardiac fibrosis in both wild-type and transgenic mice, but the extent of fibrosis was less in transgenic mice compared to wild-type mice. Moreover, basal expression levels of transforming growth factor-β were lower in transgenic mouse hearts, and it remained at lower levels after angiotensin II stimulation. These findings suggest that PDE3A protects the heart from angiotensin II-induced cardiac remodeling through its modulation of the functional connection between angiotensin II and transforming growth factor-β.

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Rats with experimentally-induced acute myocardial infarction (AMI) have proven to be a clinically relevant model for visceral pain. As there are no behavioral data available on rats in the postinfarction period, we aimed to identify specific pain-related behavioral changes following AMI to increase the validity of the model.
AMI was induced by left coronary artery ligation and pain-related behavior was analyzed using the open fi eld test (OFT) and elevated plus maze (EPM). Morphine was applied following AMI induction to differentiate pain-related changes from those related to nonspecific global changes in responsiveness. AMI was histologically confi rmed.
Hypolocomotion was consistently evident in all behavioral tests for both the infarcted group and sham group. In the OFT, both AMI and sham rats exhibited less exploratory behavior and less activity. A similar pattern of behavior was observed in EPM, where both surgical groups showed fewer entries to the open arms and spent less time in the open arms. The sham group with an intact pericardium showed the same pattern of activity as control rats. The reduction in activity and rearing observed following AMI was successfully reversed following morphine injection. This effect was abolished after naloxone application allowing us to attribute observed changes specifically to pain.
This study demonstrates that pain-related behavior in the acute postinfarction period is generally characterized by reduced mobility and explorative behavior. Our results showed that cardiac ischemia as a consequence of experimentally-induced infarction is a less important source of pain behavior than manipulation of the pericardium.

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Although survival after heart transplantation (HTx) has improved in recent years, cardiac allograft vasculopathy (CAV) is still the leading cause of remote morbidity and mortality in HTx recipients, partly because of difficulty with its diagnosis. In general, routine surveillance for CAV is advocated with coronary angiography accompanied by intravascular ultrasound (IVUS) if necessary. However, these modalities have limitations with respect to low spatial resolution, and sufficient qualitative/quantitative assessment of coronary intima has not been accomplished. Recently, optical coherence tomography (OCT) has emerged as a novel intracoronary imaging technique using an optical analogue of ultrasound with a spatial resolution of 10-20 µm, which is 10 times greater than IVUS. We here experienced a 49-year-old male who received a HTx 3 years ago, and OCT was executed during low molecular weight dextran injection. OCT demonstrated distinct double intimal layers probably consisting of a donor-transmitted atherosclerotic layer and an inner intimal proliferation due to CAV, which was indistinguishable by IVUS and virtual histological analyses. We believe that OCT imaging is not only a new loadstar during treatment of CAV but also a new generation modality for screening for early CAV in HTx recipients.

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We report an unusual case of cardiac sarcoidosis demonstrated by interventricular septal thickening. A 64-year-old woman was diagnosed with sarcoidosis involving the lungs, eyes, and skin. Three years later, renal dysfunction was detected during a periodic examination and a renal biopsy revealed non-caseating granulomas. Electrocardiogram results were normal, but an echocardiogram revealed thickening of the interventricular septum. Abnormal accumulation of gallium-67 and a perfusion defect in tecnetium-99-methoxyisobutylisonitrile scintigrams occurred in the interventricular septum. Magnetic resonance images showed T2-high intensity in the lesion. We considered the thickening to represent cardiac involvement of sarcoidosis. Oral prednisolone therapy diminished the interventricular septal thickening.

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An error appeared in the article titled “The Relationship Between Low-Density Lipoprotein Cholesterol Levels and the Incidence of Cardiovascular Disease in High-Risk Patients Treated With Pravastatin: Main Results of the AP-PROACH-J Study” by Hiroyuki Daida, et al (Vol. 55, No. 1, 39-47, 2014). “mmHg” should be inserted after “132.9/74.4-134.8/77.7” on page 42 line 10.

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