Successful resolution of a left ventricular thrombus with apixaban treatment following acute myocardial infarction.

A 62-year-old man was admitted to our emergency department owing to prolonged chest pain that had lasted for 3 h. An electrocardiogram showed ST elevation in leads I, aVL, and V1-6, and the patient's laboratory revealed elevated myocardial necrosis marker levels. Emergency coronary angiography showed total occlusion of the proximal left anterior descending coronary artery. Subsequent percutaneous coronary intervention was performed by balloon angioplasty followed by stent implantation, and the patient showed improvement. However, echocardiographic examination 2 weeks after the percutaneous coronary intervention showed a thrombus (40 × 14 mm) in the apex of the left ventricle. In addition to dual antiplatelet therapy, apixaban was administered as anticoagulant therapy for the left ventricular thrombus. The size of the thrombus gradually decreased, and magnetic resonance imaging performed approximately 6 weeks after the initial apixaban administration showed no thrombus without a thromboembolic event. This case demonstrates that left ventricular thrombus can be resolved with apixaban treatment. Apixaban may be an effective alternative to vitamin K antagonist for some patients with acute myocardial infarction complicated by left ventricular thrombus.

Role of non-electrocardiogram-gated contrast-enhanced computed tomography in the diagnosis of acute coronary syndrome.

Non-electrocardiogram-gated contrast-enhanced computed tomography (non-ECG-gated CT) is available in most hospitals where patients with chest and/or back pain are admitted to the emergency department. Although it has been established as the initial diagnostic imaging modality for acute aortic dissection (AAD) and pulmonary thromboembolism (PE), its diagnostic ability for acute coronary syndrome (ACS) in the emergency department has not been elucidated. We retrospectively investigated 154 consecutive patients who required non-ECG-gated CT to differentiate AAD and PE in the emergency department, but had no evidence of them on CT. Furthermore, a subanalysis was performed in the patients who were subsequently suspected of ACS and underwent emergent invasive coronary angiography followed by CT. We evaluated left ventricular enhancement to detect myocardial perfusion deficit by calculating Hounsfield units, and the results were compared with ultimate diagnoses and angiography findings. A perfusion deficit was detected in 43 patients, among whom 26 were ultimately diagnosed with acute myocardial infarction (AMI); 24 patients required emergent revascularization. The subanalysis indicated that perfusion abnormalities corresponded with the territory of the culprit artery in all except one patient. In the remaining 111 patients without perfusion deficit, only two required emergent revascularization, and their levels of creatine kinase MB were not elevated. The sensitivity, specificity, and positive and negative predictive values of non-ECG-gated CT in predicting AMI/emergent revascularization were 93 %, 87 %, 61 %, and 98 %/92 %, 85 %, 56 %, and 98 %, respectively. Non-ECG-gated CT facilitates the diagnosis of ACS and the decision on emergent catheterization, providing information on the ischemic myocardial area by detection of a localized decrease in left ventricular enhancement.

Eicosapentaenoic acid suppresses adverse effects of C-reactive protein overexpression on pressure overload-induced cardiac remodeling.

Serum C-reactive protein (CRP) elevation is associated with poor clinical outcome in patients with heart failure (HF). We previously reported that CRP exacerbates the development of pressure overload-induced cardiac remodeling through an enhanced inflammatory response and oxidative stress. In the present study, we examined the effect of eicosapentaenoic acid (EPA), a suppressor of inflammatory response and oxidative stress, on pressure overload-induced cardiac remodeling. Transverse aortic constriction (TAC) was performed on transgenic mice overexpressing CRP (CRPtg) and nontransgenic littermates (TAC/CON). CRPtg with TAC operation were randomly assigned to be fed a standard diet (TAC/CRPtg) or an EPA-enriched diet (7 % of total energy) (TAC/CRPtg/EPA). Myocardial mRNA level of transforming growth factor-ß1, proinflammatory cytokines, and oxidative stress markers were increased in TAC/CRPtg in comparison with TAC/CON 1 and 4 weeks after the operation. These parameters were significantly suppressed in TAC/CRPtg/EPA compared with TAC/CRPtg. In addition, after 4 weeks of EPA treatment, as compared with TAC/CRPtg, TAC/CRPtg/EPA mice demonstrated reduced heart and lung weights, increased left ventricular fractional shortening, and decreased left ventricular end-diastolic pressure, together with decreased cardiac hypertrophy, fibrosis, and improved cardiac function. In conclusion, the anti-inflammatory and antioxidative properties of EPA may make it an effective therapeutic strategy for adverse cardiac remodeling associated with CRP overexpression.

Overexpression of human C-reactive protein exacerbates left ventricular remodeling in diabetic cardiomyopathy.

BACKGROUND: C-reactive protein (CRP) is known to be a pathogenic agent in the cardiovascular system. However, the effect of CRP on heart failure has not been elucidated. The effect of human CRP on cardiac dysfunction induced by diabetes mellitus (DM) using human CRP-overexpressing transgenic mice (CRP-Tg) was examined. METHODS AND RESULTS: DM was induced in male wild-type mice (Wt/DM) and CRP-Tg (CRP/DM) by an injection of streptozotocin. Non-diabetic wild-type mice (Wt/Con) and CRP-Tg (CRP/Con) served as controls. Echocardiography and hemodynamic measurements 6 weeks after injection showed lower fractional shortening and left ventricular (LV) dP/dt max in CRP/DM compared with Wt/DM. Myocardial mRNA levels of interleukin-6, tumor necrosis factor-α, plasminogen activator inhibitor-1, angiotensin type 1 receptor, angiotensinogen, NADPH oxidase subunits (p47(phox), gp91(phox)), glutathione peroxidase-3. and connective tissue growth factor were increased in CRP/DM compared with Wt/DM. Nuclear staining of 8-hydroxydeoxyguanosine was also increased in CRP/DM compared with Wt/DM. CRP/DM was associated with increased terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling positive cells and a higher ratio of Bax/Bcl-2 proteins compared with Wt/DM. The extent of cardiac fibrosis assessed by Sirius red staining and immunohistochemical staining for collagen type 1 was significantly increased in CRP/DM compared with Wt/DM. CONCLUSIONS: Overexpression of human CRP exacerbates LV dysfunction and remodeling in diabetic cardiomyopathy, possibly through enhancement of the inflammation, renin-angiotensin system, and oxidative stress.

Successful Conservative Treatment of Cardiac Rupture Associated with Takotsubo Syndrome.

We herein report a 75-year-old woman who was diagnosed with Takotsubo syndrome (TTS) complicated by left ventricular outflow tract obstruction on admission. Treatment with beta-blocker and anticoagulant was started; however, her hemoglobin level decreased gradually, and computed tomography performed one week later revealed hemopericardium. Oozing-type cardiac rupture was suspected; therefore, we discontinued heparin treatment. Finally, she recovered uneventfully without cardiac surgery. It is noteworthy that cardiac rupture may occur with TTS, especially in patients treated with prophylactic anticoagulation therapy for apical thrombus. Furthermore, conservative, careful observation is an alternative approach in patients with oozing-type cardiac rupture associated with TTS.

Burden of Mild (<13 g/dl) Anemia in Patients With Atrial Fibrillation (A Report from a Multicenter Registry With Patient-Reported Outcomes).

The prognostic impact of anemia, especially mild anemia, in atrial fibrillation (AF) remains unclear. We examined clinical burdens of mild anemia on the quality of life (QoL) and clinical outcomes of 1,677 AF patients. Patients were divided into a non-anemia (hemoglobin [Hb] ≥13 g/dl for men and Hb ≥12 g/dl for women) and a mild anemia group (10≤ Hb <13 g/dl for men and 10≤ Hb <12 g/dl for women). At baseline, 22.5% of patients (n = 378) had anemia; patients in the mild anemia group had higher CHA2DS2-VASc scores (3.7 vs 2.7; p <0.01) and brain natriuretic peptide levels (253.5 vs 159.6 pg/ml; p <0.01) and were more likely to develop chronic kidney disease (64.2 vs 42.9%; p <0.01) than those in the non-anemia group. During follow-up (mean 1.7 ± 0.4 years), patients with mild anemia had a higher risk of heart failure hospitalization and major bleeding events than those without (12.2 vs 3.8%; p <0.01 and 5.6 vs 2.5%; p <0.01, respectively). Mild anemia was an independent risk factor for heart failure hospitalization (adjusted hazard ratio: 1.67, 95% confidence interval 1.06 to 2.62, p = 0.03) but not for major bleeding (adjusted hazard ratio: 1.44, 95% confidence interval 0.80 to 2.62, p = 0.23). QoL improvement was less likely in the mild anemia group during follow-up, despite the lack of significant differences at baseline. In conclusion, the presence of even mild anemia was associated with increased risks of heart failure hospitalization and poor QoL improvement.

Increased C-reactive protein expression exacerbates left ventricular dysfunction and remodeling after myocardial infarction.

We previously reported serum C-reactive protein (CRP) elevation after acute myocardial infarction (MI) to be associated with adverse outcomes including cardiac rupture, left ventricular (LV) remodeling, and cardiac death. Experimental studies have indicated that CRP per se has various biological actions including proinflammatory and proapoptotic effects, suggesting a pathogenic role of CRP in the post-MI remodeling process. We tested the hypothesis that increased CRP expression would exacerbate adverse LV remodeling after MI via deleterious effects of CRP. Transgenic mice with human CRP expression (CRP-Tg) and their transgene-negative littermates (control) underwent left coronary artery ligation. There was no apparent difference in phenotypic features between CRP-Tg and control mice before MI. Although mortality and infarct size were similar in the two groups, CRP-Tg mice showed more LV dilation and worse LV function with more prominent cardiomyocyte hypertrophy and fibrosis in the noninfarcted regions after MI than controls. Histological evaluation conducted 1 wk post-MI revealed a higher rate of apoptosis and more macrophage infiltration in the border zones of infarcted hearts from CRP-Tg mice in relation to increased monocyte chemotactic protein (MCP)-1 expression and matrix metalloproteinase (MMP)-9 activity. Increased CRP expression exacerbates LV dysfunction and promotes adverse LV remodeling after MI in mice. The deleterious effect of CRP on post-MI LV remodeling may be associated with increased apoptotic rates, macrophage infiltration, MCP-1 expression, and MMP-9 activity in the border zone.

Prognostic significance of acute kidney injury after reperfused ST-elevation myocardial infarction: synergistic acceleration of renal dysfunction and left ventricular remodeling.

BACKGROUND: Acute kidney injury (AKI) after myocardial infarction is associated with poor clinical outcome. However, mechanisms of the adverse effect of AKI on clinical outcome after reperfused ST-elevation myocardial infarction (STEMI) have not been fully elucidated. METHODS AND RESULTS: We examined 141 consecutive patients with reperfused first anterior STEMI. AKI was defined as an increase in serum creatinine of >or=0.3mg/dL within 48hours after admission. Patients with AKI had higher incidence of in-hospital cardiac death (P=.0004) and major adverse cardiac events (MACE, P=.020) during a mean of 39+/-40 (range, 1 to 96) months than those without, in association with adverse left ventricular (LV) remodeling. White blood cell count on admission and peak C-reactive protein were higher in patients with than those without AKI. Plasma norepinephrine on admission, interleukin-6, brain natriuretic peptide, and malondialdehyde-modified low-density lipoprotein 2 weeks after STEMI were higher in patients with AKI than those without AKI. Cox proportional hazards model analysis revealed AKI was an independent predictor of MACE (hazard ratio=2.38, P=.019). CONCLUSIONS: AKI was a strong predictor of MACE in association with adverse LV remodeling. Enhanced inflammatory response, oxidative stress, and neurohormonal activation may synergistically accelerate renal dysfunction and LV remodeling after STEMI.

Impact of systemic acidosis on the development of malignant ventricular arrhythmias after reperfusion therapy for ST-elevation myocardial infarction.

BACKGROUND: The aim of the present study was to examine the effect of systemic acidosis on the development of malignant ventricular arrhythmias, including sustained ventricular tachycardia and ventricular fibrillation (VT/VF), after reperfused ST-elevation myocardial infarction (STEMI). METHODS AND RESULTS: A total of 157 consecutive patients with a reperfused STEMI were examined. Patients were divided into 2 groups according to the presence or absence of systemic acidosis, defined as arterial blood pH <7.40 on admission. Serum creatine kinase and C-reactive protein (CRP) levels were serially measured. Systemic acidosis was observed in 53 patients (34%). There was no significant difference in coronary risk factors and arrival time from onset between the 2 groups. Estimated glomerular filtration rate (eGFR) on admission was lower in patients with acidosis than in those without (P=0.001). Patients with acidosis had a higher incidence of VT/VF (26% vs 4%, P<0.0001), especially within 48 h after STEMI (23% vs 3%, P=0.0002), than those without. The peripheral white blood cell count on admission was higher in patients with than in those without acidosis. Multivariate analysis showed that systemic acidosis was a strong independent predictor of VT/VF (relative risk =8.79, P=0.002) among variables including prior MI and eGFR <60 ml . min(-1) . 1.73 m(-2). CONCLUSIONS: Systemic acidosis was a significant determinant of VT/VF after reperfused STEMI and was associated with elevated serum CRP level. Systemic acidosis and subsequent inflammation after ischemia reperfusion may play an important role in the development of VT/VF.

Prevalence, Clinical Profile, and In-Hospital Outcomes of Sleep-Disordered Breathing in Patients Undergoing Transcatheter Aortic Valve Implantation in Japan.

Background: The prevalence, patient profile, and outcomes of sleep-disordered breathing (SDB) in aortic stenosis (AS) remain unknown, especially in East Asia. Methods and Results: One hundred and eighty-one AS patients undergoing transcatheter aortic valve implantation (TAVI) were enrolled. Sixty-one patients (33.7%) had SDB, and lower stroke volume index was an independent determinant of SDB. Incidence of in-hospital stroke after TAVI was higher in the SDB group. Conclusions: SDB is associated with left ventricular systolic dysfunction in Japanese AS patients referred for TAVI. SDB was highly associated with the incidence of stroke as a procedural complication.

Aberrant expression and potency as a cancer immunotherapy target of inhibitor of apoptosis protein family, Livin/ML-IAP in lung cancer.

CD8(+) CTLs have an essential role in immune response against tumor. Although an increasing number of tumor-associated antigens that can be recognized by CTLs have been identified from human tumors, a limited number of tumor-associated antigens is known in lung cancer. In addition, because some of them are expressed in noncancerous tissues, there exist limitations in their application to tumor immunotherapy. Livin/ML-IAP is one of recently identified inhibitor of apoptosis protein (IAP) family, which is overexpressed in melanoma cells. In this report, we show that Livin/ML-IAP is aberrantly expressed in many lung cancer cell lines and primary lung cancer tissues, whereas it is not detectable in normal tissues, including lung by reverse transcription-PCR methods. To identify HLA-A24-restricted T-cell epitopes of Livin/ML-IAP, eight peptides were selected from the amino acid sequence of this protein and screened for their binding affinity to HLA-A24. It was revealed that Livin7 peptide (amino acid sequence, KWFPSCQFLL) had the highest affinity to HLA-A24. By stimulating peripheral blood lymphocytes of HLA-A24-positive lung cancer patients with Livin7 peptide in vitro, the peptide-specific CTLs were successfully induced from four of five patients with Livin/ML-IAP-positive lung cancer but not from any of four patients without Livin/ML-IAP expression in their cancer tissues. Furthermore, the CTLs induced by Livin7 peptide showed cytotoxicity against Livin/ML-IAP(+) lung cancer cell lines in an HLA-A24-restricted manner. Our data suggest that Livin/ML-IAP may be an excellent target antigen in immunotherapy for lung cancer and Livin7 peptide may serve as a potent peptide vaccine for HLA-A*2402(+)/Livin(+) lung cancer patients.

[Acute myeloid leukemia presenting with obstructive jaundice and granulocytic sarcoma of the common bile duct].

A 55-year-old man presented with jaundice and edema of the right leg. Tests of the peripheral blood and bone marrow showed leukocytopenia with 6% blasts and 38.3% of myeloperoxidase-positive blasts, respectively. Computed tomography (CT) scanning disclosed thickening of the common bile duct wall. Granulocytic sarcomas were also found at the left chest wall and the pelvic floor. Endoscopic retrograde cholangiopancreatography confirmed the narrowing of the common bile duct. Biopsy specimens of the common bile duct and pelvic masses revealed myeloblastic infiltration. After placement of a naso-biliary drainage tube, chemotherapy consisting of cytarabine (100 mg/m2/ day for 7 days) and idarubicin (12 mg/m2/ day for 3 days) was commenced. The dose of idarubicin was not modified. No serious complications, including delayed hematopoietic recovery, were observed after chemotherapy, and a complete remission was obtained 35 days later. Jaundice and liver dysfunction also gradually improved. The patient continues to receive consolidation therapy and remains in remission 8 months after the onset of his illness.

[Successful thrombolysis without hemorrhage in a patient with cardioembolic stroke under dabigatran treatment-a case report and review of literature].

A 72-year-old male with heart failure was admitted to our hospital. Treatment with dabigatran (220 mg per day) was initiated because of atrial fibrillation. On the third day, the patient developed left-sided hemiparesis and dysarthria at 4.5 hr after the last dose of dabigatran. The activated partial thromboplastin time (APTT) was 39.1 sec, and the NIHSS (NIH Stroke Scale) was 11. An intravenous infusion of rt-PA was administered at 160 min after the onset of hemiparesis (at 7 hr after the last dose of dabigatran). Although diffusion weighted MRI revealed a minor infarction in the right lower frontal gyrus, the patient was discharged without hemorrhage (NIHSS 0), and the score on the modified Rankin scale assessed 3 months later was 0. The outcomes have been good in 8 out of 9 reported cases, including the present case; the remaining severe case developed complicating intracranial hemorrhage. Thrombolytic therapy could be safe, if it is performed more than 7 hr after the last dose of dabigatran and the APTT is less than 40 sec.

Left atrial myxoma detected after an initial diagnosis of polymyalgia rheumatica.

We herein report the case of a 69-year-old woman with left atrial myxoma detected following treatment with glucocorticoids for an initial diagnosis of polymyalgia rheumatica (PMR). The glucocorticoids markedly improved the patient's symptoms, and the tumor was excised after rapidly tapering the glucocorticoid dose. The PMR-like symptoms did not recur and the inflammatory marker levels returned to normal after surgery. The patient's clinical course indicated that the initial PMR-like symptoms were entirely caused by the left atrial myxoma. This case demonstrates that glucocorticoid treatment for suspected PMR can mask the symptoms of myxoma, leading to a delay in diagnosis.

C-reactive protein overexpression exacerbates pressure overload-induced cardiac remodeling through enhanced inflammatory response.

Serum C-reactive protein (CRP) elevation predicts the development of heart failure in patients with hypertension. CRP activates macrophages and enhances oxidative stress. We hypothesize that CRP itself has a pathogenic role in the development of pressure overload-induced cardiac remodeling. Transgenic mice with human CRP overexpression (CRPtg) and nontransgenic littermates (CON) were subjected to transverse aortic constriction (TAC/CRPtg and TAC/CON) or sham operation (Sham/CRPtg and Sham/CON). One week after operation, in TAC/CRPtg, myocardial mRNA levels of interleukin (IL)-6, CD68, glutathione peroxidase-3 (GPx3), 47-kDa α-subunit of nicotinamide adenine dinucleotide phosphate oxidase (p47(phox)), and collagen-I, the number of infiltrating Mac-2-positive macrophages, nuclear localization of phosphorylated NF-κB/p65 (p-p65) in cardiomyocytes, nuclear NF-κB-DNA-binding activity, and reactive oxygen species (ROS) content were increased compared to those in TAC/CON. Cardiac fibrosis was more prominent in TAC/CRPtg compared to TAC/CON. Four weeks after operation, heart and lung weights, cardiomyocyte cross-sectional area, and the extent of cardiac fibrosis were greater in TAC/CON than in Sham/CON, and these differences were further augmented in TAC/CRPtg compared to TAC/CON. Left ventricular (LV) fractional shortening was less and LV end-diastolic pressure was higher in TAC/CRPtg than in TAC/CON. Myocardial mRNA levels of angiotensin type 1 receptor, atrial natriuretic factor, IL-6, GPx3, p47(phox), collagen-I, and transforming growth factor (TGF)-ß1, the protein level of TGF-ß1, and the numbers of Mac-2-positive macrophages and p-p65-positive cells were higher in TAC/CRPtg than in TAC/CON. In conclusion, CRP itself may have a pathogenic role in the development of pressure overload-induced cardiac remodeling, possibly through enhanced inflammation and oxidative stress.

Human C-reactive protein exacerbates metabolic disorders in association with adipose tissue remodelling.

AIMS: C-reactive protein (CRP) expression is increased with metabolic alterations. We sought to clarify the effect of CRP on the development of obesity-induced metabolic disorders using human CRP-overexpressing transgenic mice (CRPTG). METHODS AND RESULTS: CRPTG and their non-transgenic littermates (CON) were fed a standard diet (STD) or a high-fat diet (HFD) from 6 weeks of age. Oral glucose tolerance and intraperitoneal insulin tolerance tests 12 weeks after starting the diets showed deterioration of glucose tolerance and insulin sensitivity in HFD/CRPTG compared with HFD/CON. Hepatocellular ballooning, oil droplets, and peri-sinusoidal fibrosis were more prominent in HFD/CRPTG than in HFD/CON. In HFD/CRPTG, hepatic triglyceride content was higher and serum adiponectin levels lower than in HFD/CON. Epididymal adipose tissue mRNA expression of mucin-like, hormone receptor-like 1, monocyte chemotactic protein-1, and tumour necrosis factor-α in HFD/CRPTG was up-regulated compared with that in HFD/CON. Immunohistochemical staining of epididymal adipose tissue showed that the number of Mac-3(+) macrophages was higher in HFD/CRPTG than in HFD/CON. CONCLUSION: Human CRP overexpression facilitated the development of insulin resistance and hepatosteatosis with HFD in association with adiponectin down-regulation and enhancement of macrophage infiltration and expression of pro-inflammatory cytokines in epididymal adipose tissue, suggesting its pathogenic role in the development of obesity-induced metabolic disorders.