Administration of drugs and other therapeutic agents has been the central strategy of contemporary medicine for cardiovascular disease. The use of a drug delivery system (DDS) is always demanded to enhance the efficacy and safety of therapeutic agents, and improve the signal-to-noise ratio of imaging agents. Nano-scale materials modify in vivo drug kinetics, depending on (patho)physiological mechanisms such as vascular permeability and incorporation by the mononuclear phagocyte system, which constitute ‘passive-targeting’ properties of nano-DDS. By contrast, an ‘active-targeting’ strategy employs a specific targeting structure on nano-DDS, which binds to the target molecule that is specific for a certain disease process, such as tumor specific antigens and the induction of adhesion molecules. In this review, we summarize recent studies that applied nano-DDS for the diagnosis and treatment of cardiovascular disease, especially focusing on atherosclerosis and myocardial ischemia-reperfusion (IR) injury. Pathophysiological changes in atherosclerosis and myocardial IR injury are successfully targeted by nano-DDS and preclinical studies in animals showed positive effects of nano-DDS enhancing efficacy and reducing adverse effects. The development of nano-DDS in clinical medicine is keenly being awaited.

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Immunoglobulin4 (IgG4)-related disease is a systemic inflammatory disease characterized by elevation of serum IgG4. It involves various organs such as the pancreas (autoimmune pancreatitis), lacrimal gland (Mikulicz’s disease), retroperitoneum (retroperitoneal fibrosis), aorta (aortic aneurysm and aortitis), heart (constrictive pericarditis), and pseudotumors around the coronary arteries. These disorders often coexist in accordance with progression of the disease. Because IgG4-related cardiovascular disorder affects the patient’s prognosis, early detection and treatment is important. Coronary CT imaging and echocardiography accidentally detect IgG4-related disorders and ¹⁸FDG-PET imaging can identify active inflammation in the lesions. Measurement of serum IgG4 levels and tissue biopsy are necessary for diagnosis. Minor salivary gland biopsy is recommended even though ¹⁸FDG uptake is not detected when it is difficult to obtain a biopsy specimen from IgG4-related cardiovascular lesions. The first-line treatment is high-dose corticosteroid therapy, however, relapse is often reported. Corticosteroids suppress the development of active inflammatory diseases such as aortitis, pericarditis, and pseudotumors, but already-developed lesions do not respond. A large developed aneurysm can rupture even during or after corticosteroid therapy, therefore, additional surgical treatment may be needed. Treatment of IgG4-related cardiovascular disorders might require higher doses of corticosteroids than IgG4-related extracardiovascular disorders. The adequate dose of corticosteroid, type and dose of immunosuppressant, and surgical intervention should be carefully considered on a case-by-case basis.

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The concept that coronary artery ectasia (CAE) is an inflammatory-related disease has been increasingly recognized. Periodontitis induced low-grade chronic systemic inflammation has been shown to be associated with cardiovascular diseases. The aim of the present study was to evaluate the association between periodontitis and CAE.
Thirty-two patients with isolated CAE, and 28 age, sex and smoking status-matched subjects with normal coronary arteries (NCA) underwent full dental examinations. Periodontal disease was evaluated using the following clinical parameters; number of remaining teeth, plaque index (PI), gingival index (GI), bleeding on probing (BOP), and pocket depth (PD).
Cases and controls did not differ according to their baseline characteristics and prevalence of traditional cardiovascular risk factors. Patients with isolated CAE had higher periodontal indices when compared to subjects with NCA (PD: 3.6 ± 1.26 mm versus 2.3 ± 0.79 mm; GI: 2.29 ± 0.86 versus 1.43 ± 1.19; BOP (%): 52.18 ± 20.1 versus 27.8 ± 10.9, P < 0.001, P < 0.05 and P < 0.05, respectively). Moreover, in multivariate analysis higher values for PD were found to be significant predictors for the likelihood of having coronary ectasia.
The results of the present study demonstrate for the first time that there is an association between periodontitis and isolated CAE.

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Cardiorenal anemia syndrome has recently been receiving greater attention; however, data regarding the relationship between chronic kidney disease (CKD)/anemia on presentation and in-hospital outcome in patients with acute myocardial infarction (AMI) undergoing primary percutaneous coronary intervention (PCI) are still limited in Japan.
A total of 1,447 primary PCI-treated AMI patients were classified into 4 groups according to the presence of CKD and/or anemia on hospital admission (with CKD/with anemia n = 222, with CKD/without anemia n = 299, without CKD/with anemia n = 151, without CKD/without anemia n = 775). Angiographic acute results of primary PCI were similar among the 4 groups. The patients with CKD had a significantly higher in-hospital overall mortality rate than the patients without CKD, and in the presence or absence of CKD, patients with anemia tended to have a higher in-hospital mortality rate than the patients without anemia. According to a multivariate analysis, anemia on admission was found to be an independent predictor of in-hospital mortality, whereas admission CKD and admission eGFR were statistically not independent predictors. Moreover, the multivariable adjusted odds ratio of in-hospital death in AMI patients with CKD alone was 1.855 (95% CI 0.929-3.706), and that in AMI patients with CKD/with anemia was 3.384 (95% CI 1.697-6.748).
These results suggest that among real-world, unselected Japanese AMI patients undergoing primary PCI, the combination of CKD and anemia on admission confers significant adverse effects on in-hospital mortality.

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Frequency domain optical coherence tomography (FD-OCT) provides cross-sectional images of coronary arteries and deployed stents with micron resolution and measures lumen dimensions with excellent reproducibility. FD-OCT combined with a blood flow resistances model can overcome many limitations of conventional measures of stenosis severity based on quantitative coronary angiography (QCA) and intravascular ultrasound (IVUS). The aim of this feasibility study was to investigate the relationship between pressure derived fractional flow reserve (FFR) and FD-OCT derived FFR, a new method for quantitative measure of stenosis severity that estimates the blood flow resistance and microvascular resistance of the vessel segments imaged by FD-OCT. A total of 26 coronary stenoses in 20 patients were studied consecutively with QCA, pressure derived FFR, and FD-OCT. There was a moderate but significant correlation between pressure derived FFR and FD-OCT derived FFR (r = 0.69, P < 0.001). Bland-Altman analysis showed that the mean differences between pressure derived FFR and FD-OCT derived FFR were 0.05 ± 0.14 (limits of agreement: -0.09 to 0.19). The root mean square error (RMSE) between FD-OCT derived FFR and pressure derived FFR was found to be ± 0.087 FFR units. FD-OCT derived FFR has the potential to become a valuable tool for the assessment of coronary artery stenosis.

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The aim of this study was to assess the clinical and echocardiographic predictors for the recurrence of persistent atrial fibrillation (AF) after ablation during a long-term period.
A total of 130 patients with persistent AF who had undergone radiofrequency catheter ablation (RFCA) were enrolled. We analyzed the relation between clinical parameters, echocardiographic parameters, and AF recurrences at 6 months, 1 year, and 2 years after ablation.
During the 2-year follow-up, AF recurred in 61 patients (46.6%). In the 6 month follow-up, AF recurrence was associated only with total ablation time only. However, during the 1-year and 2-year follow-up periods, the presence of hypertension, impaired left atrial (LA) emptying fraction (eF) (≤ 20%), decreased LA appendage (LAA) emptying velocity (≤ 20 cm/sec), and LAAeF (≤ 20%) were correlated with AF recurrence (odds ratio [OR] = 1.87, 2.45, 1.93, and 2.15 respectively, P = 0.016, 0.004, 0.029, and 0.004 respectively). Among these factors, impaired LAeF was the only independent predictor of AF recurrence in multivariate analysis (OR = 2.81, P = 0.012).
In patients with persistent AF who had undergone RFCA, the best predictor of AF recurrence after ablation varied according to the follow-up period. Diminished LA function was the only predictor of recurrence in the 2-year follow-up. Pre-procedural assessment of LA function might be helpful in selecting those patients who would benefit from RFCA.

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Few studies have examined the variations in longitudinal/circumferential/radial strain (LS/CS/RS) and strain rate (LSr/CSr/RSr) in individual hearts when the left ventricular ejection fraction (LVEF) has changed. We hypothesized the relationships of strain/strain rate and LVEF are not linear, but vary with multiple inflection points (IPs) in individual hearts.
Twenty-five patients with fluctuating LVEF (ΔLVEF > 10%) who had 2-D speckle tracking echocardiography available for analysis were enrolled. After models of best fit were obtained from the ‘collective’ plots to determine inflection points, the decrements of slopes above inflection points (IP) were compared with those below IPs in the ‘individual hearts’ plots.
In the ‘collective’ plots, both LS and LSr linearly decreased in proportion to LVEF when LVEF ≥ 40% but remained constant regardless of LVEF when LVEF < 40% (IPs when LVEF = 40%, P < 0.0001). The RS-LVEF relationship was sigmoid with two IPs when LVEF = 30% and 50% (P < 0.0001). However, in the ‘individual hearts’ plots, the decrements of slopes above and below IPs were not different for LS-LVEF and LSr-LVEF, and marginally different for RS-LVEF (P = 0.049, across IP when LVEF = 50%).
Collectively, the relationship of LS/LSr/RS and LVEF seemed to be not linear, but inflective, however, we could not prove the inflective relationship in individual hearts with fluctuating LVEF. Further study with more patients is needed to prove our hypothesis.

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This study was undertaken to compare the clinical results of traditional surgery and a percutaneous procedure for secundum type atrial septal defect (ASD) combined with pulmonary valve stenosis (PS). A total of 78 consecutive patients were identified between March 2004 and July 2012 in our institution. Thirty-five patients (44.9%) underwent percutaneous correction and the remaining 43 patients (55.1%) were treated surgically. All patients had simultaneous complete correction in both groups and no serious complications occurred. The surgical group was significantly younger (13.9 ± 13.0 versus 31.0 ± 17.5 years, P < 0.001) and had a longer mean hospital stay (12.6 ± 4.7 versus 5.3 ± 1.5 days, P < 0.001). There were no significant differences in defect size (18.0 ± 7.9 versus 16.9 ± 8.4 mm, P = 0.553) and transvalvular gradient detected by transthoracic echocardiography (TTE) (74.7 ± 28.3 versus 87.6 ± 37.8 mmHg, P = 0.089) between the two groups. Significant tricuspid regurgitation (TR) decreased from 66% to 14% in the transcatheter group and from 40% to 9% in the surgical group. Mild pulmonary regurgitation was detected in 8 patients in the transcatheter cohort and in 6 patients in the surgical cohort after the procedure. At last follow-up, 83% and 93% of the patients in the transcatheter and surgical groups, respectively, were free of any symptoms, and a significant improvement from preprocedure was observed in the transcatheter group but not in the surgical group (P = 0.005 and P = 0.062). In conclusion, transcatheter correction is a valuable alternative to surgery and allows more patients to be effectively treated in China.

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Patients with chronic heart failure (CHF) are frequently readmitted to the hospital due to disease progression. Although a shorter 6-minute walk distance (6MWD) is correlated with poor prognosis, 6MWD is not considered a clinical indicator for predicting hospital readmission.
We investigated whether 6MWD measured at the time of hospital discharge predicted readmission due to heart failure in CHF patients.
Patients admitted to the hospital for the first time due to heart failure were enrolled. After 6MWD was measured at discharge, patients were followed-up for 3 years. Clinical characteristics, 6MWD and readmission due to heart failure were evaluated in 252 patients (68.5 ± 11.8 years old, 162 males). Significant factors that affected readmission were extracted and cut-off values were determined using multivariate logistic regression analysis and receiver operating characteristic curves.
Of 252 CHF patients, 103 were readmitted within 3 years. 6MWD at the time of discharge was significantly shorter in readmitted patients than non-readmitted patients (P < 0.001) and was a significant predictor of readmission (P < 0.001). The odds ratio for readmission was 1.22 (P < 0.001) with each 10-meter decrease in 6MWD. The 6MWD cut-off value was determined to be 390 meters, with a sensitivity of 0.75 and a specificity of 0.77.
6MWD measured at the time of discharge is an independent predictor of hospital readmission in CHF patients, with a cut-off value of 390 meters.

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The 5-hydroxytryptamine2A receptor antagonist sarpogrelate hydrochloride exerts its effect not only by inhibition of platelet aggregation, but also by some pleiotropic effects. We have reported that a low serum lipoprotein lipase (LPL) mass level reflects insulin resistance and may be a risk factor for atherosclerotic diseases. The aim of this prospective study was to clarify the effect of sarpogrelate on serum LPL mass and cardio-ankle vascular index (CAVI) as a marker related to arterial stiffness.
Thirty-five type 2 diabetic patients (21 males and 14 females) with ankle brachial indices higher than 0.90 received sarpogrelate hydrochloride 300 mg/day for 6 months. Serum LPL mass and CAVI were measured during the study.
After 6 months of sarpogrelate hydrochloride treatment, CAVI decreased significantly (10.11 ± 0.92 to 9.87 ± 0.97, P < 0.05) and serum LPL mass increased significantly (58.2 ± 17.5 to 63.5 ± 21.4, P < 0.05). A negative correlation between change in CAVI and change in serum LPL mass was observed (r = -0.34, P < 0.05). Multiple regression analysis identified a change in serum LPL mass as a significant independent predictor for change in CAVI.
We demonstrated that sarpogrelate hydrochloride decreased CAVI accompanied by increased serum LPL mass in type 2 diabetic patients. This result suggests that sarpogrelate hydrochloride improves arterial stiffness and is a potential treatment for diabetic angiopathy.

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Sleep disordered breathing (SDB) and anemia influences the progression of chronic heart failure (CHF). Adaptive servo-ventilation (ASV) is an effective therapeutic device for treatment of CHF, however, the impacts of ASV on CHF patients with or without anemia remain unclear.
A total of 139 patients with CHF and SDB were divided into two groups: those treated with ASV (n = 53) and without ASV (n = 86). All patients were prospectively followed after discharge with the endpoints of cardiac death or progressive heart failure requiring rehospitalization. There were 65 patients (47%) with anemia among all subjects. The apnea hypopnea index was improved, and plasma BNP and high sensitive C-reactive protein levels were decreased in both groups with and without anemia by ASV therapy. The Kaplan-Meier survival curve demonstrated that the cardiac event-free rate in patients with ASV was significantly higher than in those without ASV in the anemia group (P = 0.008). However, in the non-anemia group, the cardiac event-free rate was similarly high in patients both with and without ASV (P = 0.664). Multivariate Cox proportional hazard analysis demonstrated that ASV use was an independent predictor of cardiac events in the anemia group (P = 0.0308), but not in the non-anemia group.
ASV treatment for CHF and SDB has more favorable impacts in patients with anemia than in those without anemia.

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Heart Score View (HSV) is a free software package for automated quantification of myocardial single photon emission computed tomography (SPECT) imaging using a standard Windows computer. We compared scoring results of myocardial perfusion among visual analysis, Quantitative Perfusion SPECT (QPS), and HSV in patients with known or suspected coronary artery disease.
This study included 75 consecutive patients with known or suspected coronary artery disease who underwent adenosive stress-rest Tl-201 SPECT. Analysis of myocardial perfusion SPECT was performed on a standard 17-segment model visually and using QPS and HSV.
There were 54 male and 21 female patients with a mean age of 70.5 ± 10.7 years. Thirteen patients (17%) had prior myocardial infarction. Summed stress score (SSS) and summed rest score (SRS) in the mid and basal areas were significantly higher on HSV than visual analysis or QPS. There was no significant difference in SDS in the whole area among the 3 methods. Similar results were found even in patients without prior myocardial infarction. Manual setting of the left ventricular cavity improved the correlations of SSS, SRS and SDS between HSV and the other methods.
Our data suggested that HSV was comparable with visual analysis or QPS in scoring myocardial perfusion when manual setting of the left ventricular cavity is applied.

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Coagulation factors are known to play a role in wound healing by stimulating fibroblasts and might be associated with tissue fibrosis, however, only limited data exist. Protease-activated receptor 1 (PAR1), activated by thrombin or factor (F) Xa, and PAR2, activated by FXa, have recently been reported to play roles not only in the coagulation system, but also in cardiac fibrosis. Furthermore, a previous report found that FX deficiency in mice led to the development of cardiac fibrosis. Therefore, in the present study, we evaluated cellular biological function under conditions of overexpressed thrombin and FXa in fibroblasts.
Cell migration and proliferation with FXa (1U/mL) and thrombin (1U/mL) stimulation were evaluated. Cells incubated without FXa or thrombin were used as control. H₂O₂ and TGF-β1 production were measured using ELISA. Signal pathways were evaluated using a signal pathway reporter assay.
Cell migration and proliferation were increased in FXa-stimulated cells (4.1-fold increase for migration, 1.3-fold for proliferation compared with control, respectively) and thrombin (4.1-fold increase for migration, 1.3-fold for proliferation as compared to control, respectively). H₂O₂ production was higher in FXa-stimulated cells compared to thrombin (1.3-fold increase) and control cells (1.4-fold increased). TGF-β1 production was up-regulated after FXa addition (12.6-fold increase compared with thrombin, 1.8-fold increase compared with control, respectively). In FXa-stimulated cells, AP-1 and NF-kB were increased compared to control (P < 0.05).
These data suggest that FXa and thrombin play important roles in the fibrotic process that could also lead to cardiac fibrosis, and that at least some of these signalings are more accelerated with FXa compared to thrombin.

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Impact of early bone marrow-derived mesenchymal stem cell (BMDMSC) implantation on left ventricular (LV) function after AMI was studied.
Twelve mini-pigs were equally divided into placebo (AMI through left coronary artery ligation) and cell-treated groups [BMDMSCs (3.0 × 10⁷) implanted into infarct area (IA)] with myocardium harvested by post-AMI day 90. Six healthy animals served as controls.
On post-AMI day 90, magnetic resonance imaging showed a lower LV ejection fraction but higher LV dimensions in the placebo group (P < 0.003) that also had increased IAs but reduced wall thickness (P < 0.005). Pro-apoptotic gene expressions (Bax, caspase-3) and apoptotic nucleus number in IAs and peri-IAs were highest in the placebo group (P < 0.001). Inflammatory biomarker expressions (MMP-9, oxidized protein, CD40+ cells) were highest, whereas those of angiogenesis (VEGF, CD31+ cells, SDF-1α, CXCR4) and myocardium-preservation (connexin43, troponin-I, cytochrome-C) were lowest in the placebo group (P < 0.01).
BMDMSC implantation preserved LV function and alleviated remodeling at post-AMI day 90.

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Arrhythmogenic right ventricular cardiomyopathy (ARVC) is predominantly a genetically determined heart muscle disorder that is characterized by fibro-fatty replacement of the right ventricular (RV) myocardium.¹⁾ The clinical spectrum of ARVC may represent from asymptomatic premature ventricular complexes to ventricular tachycardia (VT) and sudden cardiac death (SCD). It is a well-known leading cause of SCD in young adults.^2,3)
There is no general consensus on the management of ARVC in pregnancy, and the preferred mode of delivery is uncertain. Herein, we report a case of ARVC diagnosed at 20 weeks of gestation following a sustained VT and treated with an implantable cardiac defibrillator (ICD). We also reviewed the current knowledge and approach to ARVC in pregnancy since the literature on this condition is based on case reports.

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Previous studies have reported that the extracardiac Fontan procedure has excellent outcomes and a lower incidence of postoperative complications than the lateral tunnel procedure. However, thromboembolic events that occur after the Fontan procedure are a well-known cause of morbidity. We experienced a case of thrombosis of intra-atrial extracardiac conduit and the left pulmonary artery 2 years after a modified Fontan operation due to infective endocarditis (IE) despite prophylactic antiplatelet therapy. The patient underwent reoperation. The conduit in the right atrium (RA) was excised, and the thrombus in the vessels was removed. Because the fibrous tissue in the RA around the conduit was firm, the tissue was used as the “tunnel” for the Fontan route between the IVC and the ePTFE graft outside the RA instead of replacement using another alien graft. He was discharged on postoperative day 45 and was medicated with coumadin and aspirin. He is now being followed in our outpatient clinic and is still without any sign of infection.

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To the Editor:
We read with great interest the review article by Takahashi on the role of the NLRP3 inflammasome in acute myocardial infarction (AMI).¹⁾ The author reviewed the recent literature evaluating the role of the NLRP3 inflammasome in an animal model of AMI pointing out that the inflammatory response in which the NLRP3 inflammasome takes part is an essential part of the tissue response to injury. The NLRP3 inflammasome is activated by several stimuli produced during tissue injury or stress and, following the interaction with the ASC and the proinflammatory enzyme caspase-1, induces production of the mature forms of the pro-inflammatory cytokines IL-1β and IL18.¹⁾ As evidenced in this review, the investigation on the role of the single components of the inflammasome has generated contradictory data,¹⁾ however, the consensus is that the blockade of the NLRP3 inflammasome may be a valuable therapeutic target. Therefore, NLRP3 may be acting through two different mechanisms of inflammasome-mediated and inflammasome-independent myocardial damage.¹⁾
Several pre-clinical studies have provided evidence that targeted IL-1 signaling blockade (with one exception) is a strategy to reduce ischemic injury to the heart.²⁾ Clinical evidence is now emerging, strengthening confidence concerning the valuable use of IL-1 blockade in AMI.²⁾ Pre-clinical and clinical data show that IL-18 is a second product of the inflammasome potentially involved in myocardial injury.³⁾ However, the evidence on beneficial effects of IL-18 blockade following AMI is nowadays limited to a single study.⁴⁾ As pointed out in the review, the NLRP3 inflammasome is not only involved in the production of cytokines, but may directly participate in cardiomyocyte cell death through the activation of caspase-1.¹⁾ We agree with the author that NLRP3 is a potentially valuable target for a therapeutic intervention. We want to report that we have recently developed a novel NLRP3 inhibitor effective both in vitro and in vivo.⁵⁾ The NLRP3 inhibitor reduced ischemia reperfusion injury by reducing infarct size and by preventing caspase-1 activation, thus confirming in a preclinical animal model that NLRP3 inhibition represents a therapeutic strategy to reduce the effects of NLRP3 in the ischemic myocardium. Whether the NLRP3 inhibitor blocks both the inflammasomedependent and independent effects, however, remains to be tested in future studies.

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We thank Mezzaroma, et al for their interest in our review article,¹⁾ which describes the critical role of NLRP3 inflammasomes in inflammatory responses and tissue remodeling after myocardial infarction (MI). Moreover, we congratulate them for developing a novel pharmacological inhibitor of NLRP3 inflammasomes. According to their report,²⁾ they synthesized 16673-34-0 (5-chloro-2-methoxy-N-[2-(4-sulfamoylphenyl)ethyl]-benzamide), an intermediate in the synthesis of glyburide, that is free of the cyclohexylurea moiety involved in insulin release, and found that this compound almost completely inhibited ATP-induced IL-1β secretion in J774 macrophages and ATP-induced caspase-1 activation and cell death in HL-1 cardiomyocytes in vitro. This NLRP3 inhibitor also reduced caspase-1 activation and infarct size in a murine model of myocardial ischemia-reperfusion (I/R) injury in vivo. Furthermore, they showed that this NLRP3 inhibitor was well tolerated, with no effect on glucose levels.
Increasing evidence indicates the importance of NLRP3 inflammasomes in myocardial I/R injury. Recently, as described in our review article,¹⁾ the inflammasome-independent role of inflammasome components, such as NLRP3 and ASC, has attracted attention, especially with respect to I/R injury in several tissues. For instance, Shigeoka, et al³⁾ reported that a reduction in renal I/R injury was observed in mice deficient in NLRP3, but not in ASC or caspase-1. Because the inflammasome is defined as a molecular platform that induces caspase-1 activation, they concluded that an NLRP3-dependent, inflammasome-independent pathway may contribute to the development of I/R injury in the kidney. Similarly, we recently found that hepatic I/R injury was significantly ameliorated in NLRP3-deficient but not in ASC or caspase-1-deficient mice.⁴⁾ In this study, we further demonstrated that NLRP3 regulates chemokine-mediated neutrophil signaling and functions, which can contribute to neutrophil recruitment in the I/R liver and subsequent tissue injury.
We completely agree that the NLRP3 inhibitor recently developed by Mezzaroma, et al has great therapeutic potential for treating MI. Therefore, we would like to know whether this inhibitor could influence the inflammasome-independent functions of NLRP3. In addition, because NLRP3 inflammasomes have been shown to be involved in the process of sterile inflammation in several diseases such as gout, pseudogout, type 2 diabetes mellitus, metabolic syndrome, atherosclerosis, asbestosis, silicosis, and Alzheimer’s disease,^1,5,6) the therapeutic effects of this inhibitor in these NLRP3 inflammasome-related diseases may be of interest and should be tested in the near future.

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