今井 靖

Pulmonary tumour thrombotic microangiopathy (PTTM) is a rare complication of cancer, which can be lethal due to progressive pulmonary hypertension (PH). Several case reports have demonstrated that imatinib, a platelet-derived growth factor receptor-tyrosine kinase inhibitor, can improve severe PH in patients with PTTM. We describe the case of a 56-year-old woman. Her mean pulmonary arterial pressure (mPAP) was 47 mm Hg, and her dyspnoea worsened rapidly over several days. Although pulmonary embolism was not observed on CT, enlargement of the para-aortic lymph nodes was detected. Gastro-oesophageal endoscopy revealed signet-ring cell carcinoma. We diagnosed her as having PTTM based on her clinical course, and started treatment with imatinib. Five days after its administration, her mPAP decreased dramatically. She was discharged and lived without symptoms of PH until her death due to systemic metastasis of carcinoma. In some cases of PTTM, imatinib may be an effective therapeutic option for PH.

A 62-year-old Japanese man presented with chest pain indicating that acute myocardial infarction had occurred. Eleven years earlier, he underwent a splenectomy due to idiopathic portal hypertension. Coronary angiography revealed diffuse stenosis, with calcification in the left anterior descending coronary artery (LAD). We performed a primary percutaneous coronary intervention (PCI). We deployed two drug-eluting stents with sufficient minimal cross-sectional stent area by intravascular ultrasound and thrombolysis in myocardial infarction (TIMI) 3 flow. The initial laboratory examination revealed chronic disseminated intravascular coagulation (DIC). On the 8th hospital day, he developed chest pain indicating early coronary stent thrombosis, although he had been prescribed dual antiplatelet therapy. We performed an emergent second PCI, and the TIMI flow grade improved from 0 to 3. Clopidogrel was replaced with prasugrel. On the 18th hospital day, we detected a repeated coronary stent thrombosis again. We performed a third PCI and the TIMI flow grade improved from 0 to 3. After anticoagulation therapy with warfarin, the DIC was improved and his condition ran a benign course without the recurrence of stent thrombosis for 1 month. Contrast-enhanced CT showed portal vein thrombosis. This patient’s case reveals the possibility that the condition of chronic DIC can lead to recurrent stent thrombosis. Stent thrombosis is infrequent, but remains a serious complication in terms of morbidity and mortality. Although stent thrombosis is multifactorial, the present case suggests that DIC is a factor in stent thrombosis. To prevent stent thrombosis after PCI under DIC, anticoagulation might be a treatment option in addition to antiplatelet therapy.

Marfan syndrome (MFS) is a systemic connective tissue disorder that is caused by mutations of fibrillin-1. While MFS patients are at a high risk of periodontitis and aortic diseases, little causal information has been provided to date. To clarify the relationship, their oral condition and sinus of Valsalva (SoV) were evaluated. The subjects were patients with MFS (n = 33) who attended the University of Tokyo Hospital. We divided them into two groups; MFS patients with highly dilated (the diameters were equal to or more than 39 mm) SoV (high group, n = 18) and MFS patients with mildly dilated (less than 39 mm) SoV (mild group, n = 15). Blood examinations, echocardiograms, and full-mouth clinical measurements, including number of teeth, probing pocket depth (PPD), bleeding on probing (BOP), and community periodontal index (CPI) were performed. We found that the high group patients had greater rates of BOP compared to that of the mild group. Furthermore, the high group tended to have higher serum levels of C-reactive protein, matrix metalloproteinase-9, and transforming growth factor-beta compared to the mild group. Periodontitis may deteriorate SoV dilatation in MFS patients.

48-year-old woman underwent cardiac resynchronization therapy defibrillator implantation. Coronary sinus (CS) venography showed only one adequate anterior branch for a left ventricular lead. We were able to introduce a quadripolar left ventricular lead (Medtronic 4398-88 cm) to the distal portion of the anterior branch. Although phrenic nerve stimulation (PNS) occurred due to distal bipolar pacing (distal 1–mid 2, with 21-mm distance) and proximal pacing (mid 3–proximal 4, distance 21mm), short-spaced bipolar pacing (mid 2-3, distance 1.3 mm) did not induce PNS until 9V pacing. Shared bipolar pacing from each left ventricular electrode (distal 1 to proximal 4) as cathode and a right ventricular (RV) coil as anode resulted in PNS by 3.0V at 0.4 ms. Although quadripolar pacing could avoid PNS by switching the pacing site (ie, from distal bipolar to proximal bipolar), it might not avoid PNS in cases where the phrenic nerve and CS branch are parallel and in close proximity. We found that even though the phrenic nerve and CS branch were parallel and close, short-spaced bipolar pacing could avoid PNS. In conclusion, short-spaced bipolar pacing selected by quadripolar pacing might be beneficial to avoid PNS when the implantable branch is limited.

A 45-year-old hypertensive Japanese woman presented with epigastric pain on inspiration, fever, complete atrioventricular block and polyarthritis. Her antistreptolysin 0 levels were markedly elevated. A diagnosis of rheumatic fever was made according to the modified Jones criteria. She was prescribed loxoprofen sodium, which was partially effective for her extracardiac clinical symptoms. However, she had syncope due to complete atrioventricular block with asystole longer than 10 seconds. Consequently, we implanted a permanent pacemaker. Although we prescribed prednisolone, the efficacy of which was limited for the patient's conduction disturbance, the complete atrioventricular block persisted. In our systematic review of 12 similar cases, the duration of complete heart block was always transient and there was no case requiring a permanent pacemaker. We thus encountered a very rare case of adult-onset acute rheumatic fever with persistent complete atioventricular block necessitating permanent pacemaker implantation.

Congenital contractural arachnodactyly (CCA) is a connective tissue disease caused by mutations of the FBN2, which encodes fibrillin-2. CCA patients have a marfanoid habitus; however, aortic dilatation and/or dissection as observed in Marfan syndrome have been rarely documented. Here, we report on a Japanese familial case of CCA resulting from a FBN2 splicing mutation (IVS32+5ga), which leads to exon 32 being skipped, and the patients developed aortic dilatation and type A dissection. Although CCA patients have been believed to have favorable prognoses, repetitive aortic imaging studies must be performed in some patients to detect possible aortic disease early, and genetic testing of FBN2 might be useful to identify such high-risk patients. (c) 2015 Wiley Periodicals, Inc.

Marfan syndrome (MFS) is a systemic connective tissue disorder caused by mutations in the extracellular matrix protein fibrillin-1. While it is known that patients with MFS are at high risk of dental disorders and cardiovascular diseases, little information has been provided to date. To clarify the prevalence of periodontitis in patients with MFS, their oral condition and cardiovascular complications were evaluated. The subjects were patients with MFS (n = 40) who attended the University of Tokyo hospital; age- and gender-matched healthy individuals (n = 14) constituted a control group. Cardiovascular complications and full-mouth clinical measurements, including number of teeth, probing of pocket depth (PD), bleeding on probing (BOP), and community periodontal index (CPI) were recorded. MFS patients had more frequent cardiovascular complications (95 %) compared with the controls (0 %). MFS patients had periodontitis (CPI 3 and 4) more frequently (87.5 %) than the age- and gender-matched control subjects (35.7 %). Furthermore, MFS patients had significantly more severe periodontitis (CPI 2.90 +/- 0.12 vs 1.64 +/- 0.32) and fewer remaining teeth (26.7 +/- 0.4 vs 28.4 +/- 0.4) compared with the controls. However, PD and BOP were comparable between MFS patients and the control group. A high incidence of periodontitis and cardiovascular complications was observed in Japanese MFS patients.

Previously, we developed a new functional device (mu ELISA) by applying microfluidics and thermal-lens microscope. It has been clarified from our research that mu ELISA exhibits excellent performance for measuring human serum. However, when the analysis is performed for a very small amount of various patient samples in microliter order, differences in the composition or viscosity of each sample may effect the measurement values. In this research, the measurement conditions were determined for real patient serum by utilizing CRP. As a result, it has been confirmed that there is some effect that originates from some difference of each patient's serum. To obtain reliable measured values, it is necessary to dilute each sample by a buffer.

Despite considerable progress in preventive and therapeutic strategies, myocardial infarction (MI) is one of the leading causes of death throughout the world. A total of 55 susceptibility genes have been identified mostly in European genome-wide association studies (GWAS). Nevertheless, large-scale GWAS from other population could possibly find additional susceptibility loci. To identify as many MI susceptibility loci as possible, we performed a large-scale genomic analysis in Japanese population. To identify MI susceptibility loci in Japanese, we conducted a GWAS using 1666 cases and 3198 controls using the Illumina Human610-Quad BeadChip and HumanHap550v3 Genotyping BeadChip. We performed replication studies using a total of 11 412 cases and 28 397 controls in the Japanese population. Our study identified two novel susceptibility loci for MI: PLCL2 on chromosome 3p24.3 (rs4618210: A>G, P = 2.60 x 10(-9), odds ratio (OR) =0.91) and AP3D1-DOT1L-SF3A2 on chromosome 19p13.3 (rs3803915: A>C, P = 3.84 x 10(-9), OR = 0.89). Besides, a total of 14 previously reported MI susceptibility loci were replicated in our study. In particular, we validated a strong association on chromosome 12q24 (rs3782886: A>G: P = 1.14 x 10(-14), OR = 1.46). Following pathway analysis using 265 genes related to MI or coronary artery disease, we found that these loci might be involved in the pathogenesis of MI via the promotion of atherosclerosis. In the present large-scale genomic analysis, we identified PLCL2 and AP3D1-DOT1L-SF3A2 as new susceptibility loci for MI in the Japanese population. Our findings will add novel findings for MI susceptibility loci.

Background: Immunoglobulin G4 (IgG4)-related disease has been suggested to be involved in cardiovascular disorders such as chronic periaortitis. However, it remains unclear whether IgG4-related immuno-inflammation affects the subclinical stages of aortic remodeling. Here, we analyzed the relationship between serum IgG4 concentrations and the morphology of the ascending aorta. Methods: Serum concentrations of IgG4 were measured in 322 patients who underwent 320-slice cardiac computed tomography (CT). We assessed the aortic wall area and intravascular area at the portion between the. aortic valve and the bifurcation of the pulmonary artery. Results: In total, 174 patients (54.0%) were diagnosed to have coronary artery disease (CAD) by cardiac CT. The intravascular area was significantly larger in patients with CAD than in those without (893 mm(2) vs. 811 mm(2), p = 0.001). The aortic wall area was slightly, but not significantly, larger in patients with CAD than in those without (183 mm(2) vs. 176 mm(2), p = 0.051). Serum concentrations of IgG4 were significantly higher in patients with an aortic wall area of median or greater size (>= 181 mm(2)) than in those with a smaller area (<181 mm(2)) (32.9 mg/dL vs. 23.1 mg/dL, p = 0.026). In logistic regression analysis using age, gender, and CAD as covariates, the fourth quartile of IgG4 (>= 55.4 mg/dL) was significantly associated with an aortic wall area of median or greater size with an odds ratio of 2.09. Conclusions: Serum concentrations of IgG4 were found to be significantly associated with the aortic wall area. These findings collectively suggest that immuno-inflammatory processes may play a role in the subclinical stages of aortic remodeling. (C) 2014 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.

Aim: In an insulin-resistant state, excess lipids may accumulate in various non-adipose tissues, leading to histological and functional damage. It has been suggested that peroxisome proliferator-activated receptor-gamma (PPAR gamma) may ameliorate disorganized lipid balance. In the current study, we analyzed whether pioglitazone, an agonist of PPAR gamma, reduces angiotensin II-induced vascular lipid accumulation. Methods: Angiotensin II was infused into rats at doses of 0.7 mg/kg/day via a subcutaneously implanted osmotic minipump for 7 consecutive days. Pioglitazone was orally given at a dose of 2.5 mg/kg/day for 7 days. Results: Pioglitazone significantly reduced angiotensin II-induced enhanced lipid deposition and superoxide production in the adventitia of the aorta, as detected by oil red O and dihydroethidium (DHE) staining, respectively. Increased DHE signals, some observed at the site of lipid deposition, were mainly localized in ED-1-positive monocytes/macrophages. Angiotensin II-induced upregulation of the expression of LDL receptor and Nox1 was inhibited by pioglitazone treatment. In addition, angiotensin II significantly reduced the expression of PCSK9, and this reduction was ameliorated by pioglitazone. On the other hand, pioglitazone did not significantly alter the expression of the phosphorylated forms of AMPK alpha and ACC, which was downregulated by angiotensin II. Conclusions: Pioglitazone treatment suppressed excess lipid accumulation and superoxide production in the aorta in an angiotensin II-induced rat model of hypertension.

Marfan syndrome is an autosomal dominant heritable disorder of the connective tissue, caused by mutations of the gene FBN1, which encodes fibrillin-1, a major component of the microfibrils of the extracellular matrix. Fibrillin-1 interacts with transforming growth factor- (TGF-), and dysregulated TGF- signaling plays a major role in the development of connective tissue disease and familial aortic aneurysm and dissection, including Marfan syndrome. Losartan, an angiotensin II blocker, has the potential to reduce TGF- signaling and is expected to be an additional therapeutic option. Clinical diagnosis is made using the Ghent nosology, which requires comprehensive patient assessment and has been proven to work well, but evaluation of some of the diagnostic criteria by a single physician is difficult and time-consuming. A Marfan clinic was established at the University of Tokyo Hospital in 2005, together with cardiologists, cardiac surgeons, pediatricians, orthopedists, and ophthalmologists in one place, for the purpose of speedy and accurate evaluation and diagnosis of Marfan syndrome. In this review, we discuss the recent progress in diagnosis and treatment of Marfan syndrome, and the characteristics of Japanese patients with Marfan syndrome.

Marfan syndrome is an inherited disorder characterized by genetic abnormality of microfibrillar connective tissue proteins. Endothelial dysfunction is thought to cause aortic dilation in subjects with a bicuspid aortic valve; however, the role of endothelial dysfunction and endothelial damaging factors has not been elucidated in Marfan syndrome. Flow-mediated dilation, a noninvasive measurement of endothelial function, was evaluated in 39 patients with Marfan syndrome. Aortic diameter was measured at the aortic annulus, aortic root at the sinus of Valsalva, sinotubular junction and ascending aorta by echocardiography, and adjusted for body surface area (BSA). The mean value of flow-mediated dilation was 6.5 +/- A 2.4 %. Flow-mediated dilation had a negative correlation with the diameter of the ascending thoracic aorta (AscAd)/BSA (R = -0.39, p = 0.020) and multivariate analysis revealed that flow-mediated dilation was an independent factor predicting AscAd/BSA, whereas other segments of the aorta had no association. Furthermore, Brinkman index had a somewhat greater influence on flow-mediated dilation (R = -0.42, p = 0.008). Although subjects who smoked tended to have a larger AscAd compared with non-smokers (AscA/BSA: 17.3 +/- A 1.8 versus 15.2 +/- A 3.0 mm/m(2), p = 0.013), there was no significant change in flow-mediated dilation, suggesting that smoking might affect aortic dilation via an independent pathway. Common atherogenic risks, such as impairment of flow-mediated dilation and smoking status, affected aortic dilation in subjects with Marfan syndrome.

INTRODUCTION: Results from the multicenter trial (J-Land study) of landiolol versus digoxin in atrial fibrillation (AF) and atrial flutter (AFL) patients with left ventricular (LV) dysfunction revealed that landiolol was more effective for controlling rapid HR than digoxin. The subgroup analysis for patient characteristics was conducted to evaluate the impact on the efficacy and safety of landiolol compared with digoxin. METHODS: Two hundred patients with AF/AFL, heart rate (HR) ≥ 120 beats/min, and LV ejection fraction (LVEF) 25-50% were randomized to receive either landiolol (n = 93) or digoxin (n = 107). Successful HR control was defined as ≥20% reduction in HR together with HR < 110 beats/min at 2 h after starting intravenous administration of landiolol or digoxin. The subgroup analysis for patient characteristics was to evaluate the impact on the effectiveness of landiolol in AF/AFL patients complicated with LV dysfunction. RESULTS: The efficacy in patients with NYHA class III/NYHA class IV was 52.3%/35.3% in landiolol, and 13.8%/9.1% in digoxin (p < 0.001 and p = 0.172), lower LVEF (25-35%)/higher LVEF (35-50%) was 45.7%/51.1% in landiolol, and 14.0%/12.7% in digoxin (p < 0.001 and p < 0.001), CKD stage 1 (90 < eGFR)/CKD stage 2 (60 ≤ eGFR < 90)/CKD stage 3 (30 ≤ eGFR < 60)/CKD stage 4 (15 ≤ eGFR < 30) was 66.7%/59.1%/39.6%/66.7% in landiolol, and 0%/13.8%/17.0%/0% in digoxin (p = 0.003, p < 0.001, p = 0.015 and p = 0.040). CONCLUSIONS: This subgroup analysis indicated that landiolol was more useful, regardless of patient characteristics, as compared with digoxin in AF/AFL patients complicated with LV dysfunction. Particularly, in patients with impaired renal function, landiolol should be preferred for the purpose of acute rate control of AF/AFL tachycardia.

Background: Although periodontitis is a risk factor for cardiovascular disease (CVD), the influence of periodontitis on Marfan syndrome (MFS) with CVD is unclear. The aim of this study was to assess the relationship between periodontal bacterial burden and MSF with CVD. Methods and Results: The subjects were patients with MFS with CVD (n = 47); age and gender matched non-MFS CVD patients (n = 48) were employed as controls. Full-mouth clinical measurements, including number of teeth, probing of pocket depth (PD), bleeding on probing (BOP) and community periodontal index (CPI) were recorded. We also evaluated the existence of three periodontal pathogens, Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, and Prevotella intermedia using polymerase chain reaction assays. Serum antibody titers against the pathogens were also measured. We revealed that MFS with CVD patients had periodontitis more frequently than the age and gender matched non-MFS CVD control subjects. MFS with CVD patients had significantly severer periodontitis, fewer remaining teeth and deeper PD compared to the non-MFS CVD controls. Furthermore, the serum antibody titer level against Prevotella intermedia was significantly lower in MFS plus CVD patients compared to the non-MFS CVD patients. Conclusion: Periodontitis may influence the pathophysiology of cardiovascular complications in MFS patients. A specific periodontal pathogen might be a crucial therapeutic target to prevent CVD development.

Objectives: Immunoglobulin G4 (IgG4)-related immuno-inflammation may play a role in the development of coronary artery disease (CAD). We analyzed the association of serum IgG4 and soluble interleukin-2 receptor (sIL-2R) levels with epicardial fat volume (EFV) and coronary artery calcification (CAC). Methods: Serum IgG4 and sIL-2R levels were measured in 267 patients who underwent 320-slice cardiac computed tomography. Results: The median serum levels of IgG4 and sIL-2R were higher in patients with CAD than in those without. Serum IgG4 levels were significantly greater in patients with EFV within the second and fourth quartile (75 mL) than in those with low EFV (&lt;75 mL) (33.5 mg/dL vs. 22.5 mg/dL). On the other hand, serum sIL-2R levels were significantly higher in patients with CAC than in those without (409 U/mL vs. 345 U/mL). In age- and gender-adjusted logistic regression analysis, the fourth quartile of IgG4 (&gt;= 56.7 mg/dL) was associated with EFV within the second and fourth quartile (&gt;= 75 mL) with an odds ratio of 3.13. Conclusion: Serum IgG4 levels were greater in patients with EFV within the second and fourth quartile, whereas serum sIL-2R levels were increased in patients with CAC. These two biomarkers may reflect different mechanisms underlying development of cardiovascular remodeling. (C) 2013 Elsevier B.V. All rights reserved.

Objectives: Immunoglobulin G4 (IgG4)-related immuno-inflammation may play a role in the development of coronary artery disease (CAD). We analyzed the association of serum IgG4 and soluble interleukin-2 receptor (sIL-2R) levels with epicardial fat volume (EFV) and coronary artery calcification (CAC). Methods: Serum IgG4 and sIL-2R levels were measured in 267 patients who underwent 320-slice cardiac computed tomography. Results: The median serum levels of IgG4 and sIL-2R were higher in patients with CAD than in those without. Serum IgG4 levels were significantly greater in patients with EFV within the second and fourth quartile (75 mL) than in those with low EFV (&lt;75 mL) (33.5 mg/dL vs. 22.5 mg/dL). On the other hand, serum sIL-2R levels were significantly higher in patients with CAC than in those without (409 U/mL vs. 345 U/mL). In age- and gender-adjusted logistic regression analysis, the fourth quartile of IgG4 (&gt;= 56.7 mg/dL) was associated with EFV within the second and fourth quartile (&gt;= 75 mL) with an odds ratio of 3.13. Conclusion: Serum IgG4 levels were greater in patients with EFV within the second and fourth quartile, whereas serum sIL-2R levels were increased in patients with CAC. These two biomarkers may reflect different mechanisms underlying development of cardiovascular remodeling. (C) 2013 Elsevier B.V. All rights reserved.

Vascular endothelial growth factor-A (VEGF-A) is one of the major angiogenic factors, and its actions are primarily mediated through its two membrane receptors, VEGFR-1 and VEGFR-2. A soluble form of VEGFR-1 (sVEGFR-1) sequesters the free form of VEGF-A, and acts as a potent anti-angiogenic factor. While sVEGFR-1 is synthesized as a splice variant of VEGF-R1 gene, the interactions between VEGF-A and sVEGFR-1 remain largely unknown. Here, we show that VEGF-A upregulates sVEGF-R1 expression in human vascular endothelial cells but leaves full-length VEGF-R1 expression unchanged, and that this induction was dependent on the VEGFR-2-protein kinase C-MEK signaling pathway. The VEGF-A-induced sVEGFR-1 upregulation can operate as a negative feedback system, which if modulated can become a novel therapeutic target for regulating pathological angiogenesis. (C) 2013 Federation of European Biochemical Societies. Published by Elsevier B. V. All rights reserved.

Vascular endothelial function is impaired in hypercholesterolemia partly because of injury by modified LDL. In addition to modified LDL, free cholesterol (FC) is thought to play an important role in the development of endothelial dysfunction, although the precise mechanisms remain to be elucidated. The aim of this study was to clarify the mechanisms of endothelial dysfunction induced by an FC-rich environment. Loading cultured human aortic endothelial cells with FC induced the formation of vesicular structures composed of FC-rich membranes. Raft proteins such as phospho-caveolin-1 (Tyr-14) and small GTPase Rac were accumulated toward FC-rich membranes around vesicular structures. In the presence of these vesicles, angiotensin II-induced production of reactive oxygen species (ROS) was considerably enhanced. This ROS shifted endothelial NOS(eNOS) toward vesicle membranes and vesicles with a FC-rich domain trafficked toward perinuclear late endosomes/lysosomes, which resulted in the deterioration of eNOS Ser-1177 phosphorylation and NO production. Angiotensin II-induced ROS decreased the bioavailability of eNOS under the FC-enriched condition.

We report a case of aortic stenosis associated with ochronosis in a 70-year-old man who underwent biologic aortic valve replacement. Intraoperative findings included ochronosis of a severely calcified pigmented aortic valve along with pigmentation of the intima of the aorta. © 2013 The Society of Thoracic Surgeons.

Background Recent studies, supported by advances in computer science, have successfully simulated the excitation and repolarization processes of the heart, based on detailed cell models of electrophysiology and implemented with realistic morphology. Methods In this study, we extend these approaches to simulate the body surface electrocardiogram (ECG) of specific individuals. Patient-specific finite element models of the heart and torso are created for four patients with various heart diseases, based on clinical data including computer tomography, while the parallel multi-grid method is used to solve the dynamic bi-domain problem. Personalization procedures include demarcation of nonexcitable tissue, allocation of the failing myocyte model of electrophysiology, and modification of the excitation sequence. In particular, the adjustment of QRS morphology requires iterative computations, facilitated by the simultaneous visualization of the propagation of excitation in the heart, average QRS vector in the torso, and 12-lead ECG. Results In all four cases we obtained reasonable agreement between the simulated and actual ECGs. Furthermore, we also simulated the ECGs of three of the patients under bi-ventricular pacing, and once again successfully reproduced the actual ECG morphologies. Since no further adjustments were made to the heart models in the pacing simulations, the good agreement provides strong support for the validity of the models. Conclusions These results not only help us understand the cellular basis of the body surface ECG, but also open the possibility of heart simulation for clinical applications. (PACE 2013; 36:309-321)

Although hypertrophic cardiomyopathy (HCM) with an accessory pathway is encountered in clinical practice, there is little evidence of a coherent strategy for ablation of the accessory pathway in patients with HCM. We present the case of a 61-year-old man who had type B Wolff-Parkinson-White (WPW) syndrome with hypertrophic obstructive cardiomyopathy (HOCM). Due to paroxysmal atrial fibrillation, he underwent radiofrequency catheter ablation of the accessory pathway located in the right postero-lateral wall to prevent secondary symptomatic events. His LV dyssynchrony improved after the procedure, but the degree of the LV outflow tract (LVOT) pressure gradient was increased. To stabilize the LVOT pressure gradient, he needed additional medications. This case shows that patients with HOCM should be carefully evaluated before making a decision concerning ablation of the accessory pathway.

Background: Cardiac resynchronization therapy/defibrillators (CRTD) and implantable cardioverter defibrillators (ICD) with continuous intrathoracic impedance monitoring might provide an early warning of thoracic fluid retention. In contrast, volume loss events such as dehydration and bleeding are also common events in heart failure patients treated with diuretics and anticoagulants. The correlation between intrathoracic impedance and a volume loss event is not known. Methods and Results: This study evaluated the association between intrathoracic impedance and volume loss events in 36 patients with chronic heart failure (New York Heart Association [NYHA] II, III and IV) who had received CRTD/ICD implantation. Elevation of thoracic impedance above the reference line was defined as a positive deviation of thoracic impedance (PDI). This study recorded 249 PDIs including 60 spike PDIs defined as over 5 ohms elevation from the reference line and 17 large PDIs as over 5 ohms elevation and continuing for at least 4 days. Clinically, 96 dehydration events and 2 bleeding events were observed over a 1-year period. The sensitivity and positive predictive value (PPV) for spike PDI was 31.6% and 51.7%, respectively, while those for large PDI were 17.3% and 100%, respectively. Conclusions: A large PDI reflected dehydration and bleeding events with a high PPV in severe heart failure patients. The large PDI criteria might therefore be useful for predicting volume loss events in chronic heart failure patients. (Circ J 2012; 76: 2592-2598)

Modulator recognition factor-2 (Mrf2/AT-rich interaction domain (Arid)5b) has been revealed to be involved in pathogenesis of atherosclerosis and adipogenesis. Single-nucleotide polymorphisms (SNPs) in the MRF2/ARID5B gene are associated with coronary artery disease (CAD) and has been proposed as a candidate gene for type 2 diabetes (T2D). The study was aimed to determine whether any of the four MRF2/ARID5B SNPs (rs2893880, rs10740055, rs7087507 and rs10761600) associated with susceptibility to CAD are also associated with T2D, and to determine whether SNP genotype influences the levels of adiponectin and other clinical factors. Association of MRF2/ARID5B SNPs was investigated in 500 diabetic patients from the Department of Metabolic Diseases at the University of Tokyo and 243 hospital-based nondiabetic individuals from the Institute for Adult Disease Asahi Life Foundation Hospital and 500 community-based nondiabetic individuals from the Hiroshima Atomic Bomb Casualty Council Health Management Center. Associations of haplotypes of these SNP with levels of adiponectin and other clinical factors were evaluated when the data was available. We found rs2893880C, rs10740055A, rs7087507A and rs10761600T were increasingly associated with T2D in terms of allele/genotype frequencies of each SNP and their haplotype combinations. Individuals with haplotype CAAT indicated an 1.86 times higher prevalence of diabetes compared with individuals with GCGA (OR 1.86 (95% confidence interval (CI) 1.43-2.41)). Furthermore, CAAT significantly associated with adiponectin levels and other clinical factors. In conclusion, polymorphisms on the MRF2/ARID5B gene were associated with susceptibility to T2D as well as adiponectin and other clinical factors, which was in a completely concordant way with their associations with CAD. Journal of Human Genetics (2012) 57, 727-733; doi:10.1038/jhg.2012.101; published online 13 September 2012

Refractory ventricular tachyarrhythmias are life threatening, especially in patients with stage D heart failure, and left ventricular assist device therapy is virtually the sole option to resolve the fatal conditions in many cases. The Interagency Registry for Mechanically Assisted Circulatory Support defines modifier A as complicating recurrent ventricular tachyarrhythmias. However, the optimal timing to implant a left ventricular assist device remains to be determined in less sick patients with modifier A. We experienced three patients with stage D heart failure with revised modifier A, i.e., at least two appropriate operations of implantable cardiac defibrillators within 2 weeks. Two of them were rescued by extracorporeal left ventricular assist device implantation, but one died because of an electrical storm before left ventricular assist device support was available. We would like to emphasize that we should consider implantable left ventricular assist device therapy as soon as possible for those who are assigned modifier A to prevent sudden arrhythmic death.

Background: Little is known about depressive symptoms in heart failure with preserved ejection fraction (HFpEF, EF &gt;= 50%). We aimed to assess the prevalence of depression, to clarify the impact of depressive symptoms upon clinical outcomes. and to identify factors associated with these symptoms in HF with reduced EF (HFrEF, EF &lt;50%) and HFpEF. Methods and results: A total of 106 HF outpatients were enrolled. Of them, 61 (58%) had HFpEF. Most patients were male (HFrEF 80%, HFpEF 70%) and the mean of plasma B-type natriuretic peptide (BNP) level in the HFrEF group was similar to that in the HFpEF group (164.8 +/- 232.8 vs. 98.7 +/- 94.8 pg/mL). HFrEF patients were treated more frequently with beta-blockers compared with HFpEF patients (71% vs. 43%, p = 0.004). Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression Scale (CES-D). The prevalence of depression (CES-D score &gt;= 16), and CES-D score did not significantly differ between HFrEF and HFpEF (24% vs. 25%, 14.1 +/- 8.3 vs. 12.1 +/- 8.3, respectively). During the 2-year follow-up, depressed patients had more cardiac death or HF hospitalization in HFrEF (55% vs. 12%, p = 0.002) and HFpEF (35% vs. 11%, p = 0.031). Cox proportional hazard analysis revealed that a higher CES-D score, indicating increased depressive symptoms, predicted cardiac events independent of BNP in HFrEF [hazard ratio (HR) 1.07, 95% confidence interval (CI) 1.01-1.131 and HFpEF (HR 1.09, 95%CI 1.04-1.15). Multiple regression analyses adjusted for BNP showed that independent predictors of depressive symptoms were non-usage of beta-blockers and being widowed or divorced in HFrEF. On the other hand, usage of warfarin was the only independent risk factor for depressive symptoms in HFpEF (all, p &lt; 0.05). Conclusions: Depressive symptoms are common and independently predict adverse events in HFrEF/HFpEF patients. This study suggests that beta-blockers reduce depressive symptoms in HFrEF. In contrast, treatment for depression remains to be elucidated in HFpEF. (c) 2012 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.

The cardiovascular system may be involved as a target organ of multifocal fibrosclerosis, which may manifest as idiopathic retroperitoneal fibrosis, inflammatory aortic aneurysm, inflammatory periarteritis, and inflammatory pericarditis. These pathological conditions can sometimes occur concomitantly. Idiopathic retroperitoneal fibrosis and inflammatory abdominal aortic aneurysm are both characterized by the presence of fibro-inflammatory tissue around the abdominal aorta expanding into the surrounding retroperitoneal structures, and together they may be termed 'chronic periaortitis'. Cardiovascular fibrosclerosis has become non-uncommonly encountered condition since imaging modalities have made its diagnosis more feasible. In addition, recent studies have demonstrated that a certain fraction, but not all, of cardiovascular fibrosclerosis may have a link with immunoglobulin-G4 (IgG4)-related sclerosing disease (IgG4-SD). IgG4-SD is histologically characterized by dense fibrosclerosis and infiltration of lymphocytes and IgG4-positive plasma cells, and these histopathologic findings seem to be essentially similar regardless of the organs involved. In this mini review, we summarize what is known so far about multifocal fibrosclerosis of the cardiovascular system and its association with IgG4-SD, and what remains to be clarified in future investigations. (C) 2011 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.

Background: Immunoglobulin G4 (IgG4)-related immuno-inflammation has been suggested to play a role in the development of remodeling of arterial wall. We investigated the association between serum concentrations of IgG4 or soluble interleukin-2 receptor (sIL-2R) and coronary artery disease (CAD). Methods: Serum concentrations of IgG4 and sIL-2R were measured in 286 patients who underwent coronary angiography. Results: In patients with CAD, the medians of serum concentrations of IgG4 (393 mg/dl) and sIL-2R (388 U/ml) were significantly higher than corresponding values in patients without CAD (IgG4 27.0 mg/dl, sIL-2R 312 U/ml). In receiver-operating characteristic curve analysis, the area under the curve of sIL-2R and IgG4 for the presence of CAD was 0.634 and 0.632, respectively. Age- and gender-adjusted logistic regression analysis showed that both of the fourth quartile of sIL-2R concentrations (&gt;= 509 U/ml) and that of IgG4 concentrations (&gt;= 57.7 mg/dl) were found to be associated with CAD with an odds ratio of 2.82 and 4.08, respectively, compared with the corresponding lowest quartile. Conclusions: Serum concentrations of IgG4 and sIL-2R were increased in patients with angiographically-proven CAD, suggesting that IgG4-related immuno-inflammation may also have a role in the development and/or progression of coronary artery atherosclerosis. (C) 2011 Elsevier B.V. All rights reserved.

Retroperitoneal fibrosis, inflammatory aortic aneurysm, and pericardial and mediastinal fibrosis are characterized by infiltration of immuno-inflammatory cells and deposition of thickened fibrous tissues. Several recent studies suggested that an immunoglobulin-G4 (IgG4)-related immunological mechanism may play a role in these diseases. By searching the clinical database of patients admitted to our department between 2000 and 2010, we summarized the clinical data of 11 patients who were diagnosed to have these disorders. The diagnoses were idiopathic retroperitoneal fibrosis (8 cases), mediastinal and/or pericardial fibrosis (4 cases), inflammatory abdominal aneurysm (2 cases), and inflammatory coronary periarteritis (1 case). Hypertension, diabetes, and dyslipidemia were found in 45%, 36%, and 55%, respectively, in these patients, and they were all either current or former smokers. Two patients with pericardial involvement showed a rushed clinical course, resulting in in-hospital death. Serum levels of IgG were elevated in 67%, and soluble interleukin-2 receptor was elevated in 75%, when measured. Immunohistochemical analysis showed marked infiltration of IgG4-positive plasma cells in the pericardium in patients who died of constrictive pericarditis. Our data support the notion that immune-inflammatory mechanism, which might be IgG4-related sometimes, may play a role in idiopathic retroperitoneal fibrosis, inflammatory aortic aneurysm, and mediastinal/pericardial fibrosis, although clinical course may differ substantially. (C) 2011 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.

We report on a 64-year-old female patient who underwent cardiac surgery for left atrial myxoma, using the superior septal approach with large atrial septal wall resection and patch closure. The superior septal approach is reported to be a relatively safe method for preventing the development of sinus node dysfunction after cardiac surgery. However, this patient developed sinus node dysfunction after surgery and required the implantation of a permanent pacemaker. Moreover, in this case, determining the appropriate positions of the pacemaker leads was difficult because of the presence of a large conduction delay in the interatrium. Selecting the appropriate atrioventricular delay settings was important in order to achieve proper sequential contractions between the left atrium and the left ventricle. © 2012 Japanese Heart Rhythm Society.

An increase in short-term blood pressure (BP) variability is a characteristic feature in the elderly. It makes the management of hemodynamics more difficult, because it is frequently seen disturbed baro-reflex function and increased arterial stiffness, leading to isolated systolic hypertension. Large BP variability aggravates hypertensive target organ damage and is an independent risk factor for the cardiovascular (CV) events in elderly hypertensive patients. Therefore, appropriate control in BP is indispensable to manage lifestyle-related diseases and to prevent subsequent CV events. In addition, accumulating recent reports show that excessive BP variability is also associated with a decline in cognitive function and fall in the elderly. In the clinical settings, we usually evaluate their health condition, mainly with single point BP measurement using cuff inflation. However, unfortunately we are not able to find the close changes in BP by the traditional way. Here, we can show our advantageous approach of continuous BP monitoring using newly developing device `wearable BP sensing&#039; without a cuff stress in the elderly. The new device could reflect systolic BP and its detailed changes, in consistent with cuff-based BP measurement. Our new challenge suggests new possibility of its clinical application with high accuracy.

Wolff-Parkinson-White syndrome is associated with heart failure (HF) mainly via tachycardia. Several case report series have suggested dyssynchrony due to an accessory pathway as a possible cause of HF even in the absence of tachyarrhythmias. The role of cardiac resynchronization in the suppression of anterograde conduction of accessory pathways by catheter ablation or pharmacotherapy in such patients remains unclear, especially in the pediatric population. We describe an infant case with HF due to ventricular dyssynchrony and refractory tachycardia caused by a right anterolateral accessory pathway. Cardiac resynchronization either by catheter ablation or amiodarone appears to be of value in such cases. Copyright (c) 2012 S. Karger AG, Basel

Marfan syndrome (MS) is an inherited connective tissue disorder, and detailed evaluations of multiple organ systems are required for its diagnosis. Genetic testing of the disease-causing fibrillin-1 gene (FBN1) is also important in this diagnostic scheme. The aim of this study was to define the clinical characteristics of Japanese patients with MS and enable the efficient and accurate diagnosis of MS with mutational analysis using a high-throughput microarray-based resequencing system. Fifty-three Japanese probands were recruited, and their clinical characteristics were evaluated using the Ghent criteria. For mutational analysis, an oligonucleotide microarray was designed to interrogate FBN1, and the entire exon and exon-intron boundaries of FBN1 were sequenced. Clinical evaluation revealed more pulmonary phenotypes and fewer skeletal phenotypes in Japanese patients with MS compared to Caucasians. The microarray-based resequencing system detected 35 kinds of mutations, including 23 new mutations The mutation detection rate for patients who fulfilled the Ghent criteria reached 71%. Of note, splicing mutations accounted for 19% of all mutations, which is more than previously reported. In conclusion, this comprehensive approach successfully detected clinical phenotypes of Japanese patients with MS and demonstrated the usefulness and feasibility of this microarray-based high-throughput resequencing system for mutational analysis of MS. (C) 2011 Elsevier Inc. All rights reserved. (Am J Cardiol 2011;108:1801-1807)

Procedure-related coronary dissection is associated with an increased risk of major adverse cardiovascular events after percutaneous coronary intervention (PCI). In most patients with such an iatrogenic complication, further PCI or bypass surgery aimed at complete revascularization is performed. Moreover, conventional coronary angiography has been used as a standard modality in the follow-up of such patients. The present report describes a 70 year old female patient who was complicated by catheter-related extensive coronary dissection in the right coronary artery (RCA) when treated for an acute myocardial infarction. Although RCA flow was insufficient, we decided against revascularization and followed her medically without additional revascularization procedures. Her clinical course had been uneventful for 4 years. However, symptoms of effort angina developed and re-examinations were performed at approximately 5 years after the myocardial infarction. Although conventional coronary angiography failed to show the culprit lesion responsible for the angina symptoms, the superior spatial resolution of the coronary CT angiography clearly identified significant progression of the stenotic lesion in the true lumen of the dissected RCA. Thus, coronary CT angiography might be considered as a possible first-line follow-up modality in patients with procedure-related coronary dissection. (Int Heart J 2011; 52: 240-242)

Hypertension is a typical modern lifestyle-related disease that is closely associated with the development of cardiovascular disorders. Elevation of angiotensin II (ANG II) is one of several critical factors for hypertension and heart failure; however, the mechanisms underlying the ANG II-mediated pathogenesis are still poorly understood. Here, we show that ANG II-mediated cardiac fibrosis, but not hypertrophy, is regulated by interferon regulatory factor 3 (IRF3), which until now has been exclusively studied in the innate immune system. In a ANG II-infusion mouse model (3.0 mg/kg/d), we compared IRF3-deficient mice (Irf3(-/-)/Bcl2l12(-/-)) with matched wild-type (WT) controls. The development of cardiac fibrosis [3.95 +/- 0.62% (WT) vs. 1.41 +/- 0.46% (Irf3(-/-)/Bcl2l12(-/-)); P &lt; 0.01] and accompanied reduction in left ventricle end-diastolic dimension [2.89 +/- 0.10 mm (WT) vs. 3.51 +/- 0.15 mm (Irf3(-/-)/Bcl2l12(-/-)); P=0.012] are strongly suppressed in Irf3(-/-)/Bcl2l12(-/-) mice, whereas hypertrophy still develops. Further, we provide evidence for the activation of IRF3 by ANG II signaling in mouse cardiac fibroblasts. Unlike the activation of IRF3 by innate immune receptors, IRF3 activation by ANG II is unique in that it is activated through the canonical ERK signaling pathway. Thus, our present study reveals a hitherto unrecognized function of IRF3 in cardiac remodeling, providing new insight into the progression of hypertension-induced cardiac pathogenesis.-Tsushima, K., Osawa, T., Yanai, H., Nakajima, A., Takaoka, A., Manabe, I., Ohba, Y., Imai, Y., Taniguchi, T., Nagai, R. IRF3 regulates cardiac fibrosis but not hypertrophy in mice during angiotensin II-induced hypertension. FASEB J. 25, 1531-1543 (2011). www.fasebj.org