AimThere is an unmet need to develop an innovative cardioprotective modality for acute myocardial infarction (AMI), for which the effectiveness of interventional reperfusion therapy is hampered by myocardial ischemia-reperfusion (IR) injury. Pretreatment with statins before ischemia is shown to reduce MI size in animals. However, no benefit was found in animals and patients with AMI when administered at the time of reperfusion, suggesting insufficient drug targeting into the IR myocardium. Here we tested the hypothesis that nanoparticle-mediated targeting of pitavastatin protects the heart from IR injury.Methods and ResultsIn a rat IR model, poly(lactic acid/glycolic acid) (PLGA) nanoparticle incorporating FITC accumulated in the IR myocardium through enhanced vascular permeability, and in CD11b-positive leukocytes in the IR myocardium and peripheral blood after intravenous treatment. Intravenous treatment with PLGA nanoparticle containing pitavastatin (Pitavastatin-NP, 1 mg/kg) at reperfusion reduced MI size after 24 hours and ameliorated left ventricular dysfunction 4-week after reperfusion; by contrast, pitavastatin alone (as high as 10 mg/kg) showed no therapeutic effects. The therapeutic effects of Pitavastatin-NP were blunted by a PI3K inhibitor wortmannin, but not by a mitochondrial permeability transition pore inhibitor cyclosporine A. Pitavastatin-NP induced phosphorylation of Akt and GSK3β, and inhibited inflammation and cardiomyocyte apoptosis in the IR myocardium.ConclusionsNanoparticle-mediated targeting of pitavastatin induced cardioprotection from IR injury by activation of PI3K/Akt pathway and inhibition of inflammation and cardiomyocyte death in this model. This strategy can be developed as an innovative cardioprotective modality that may advance currently unsatisfactory reperfusion therapy for AMI.

Myocardial ischemia-reperfusion (IR) injury limits the therapeutic effect of early reperfusion therapy for acute myocardial infarction (AMI), in which the recruitment of inflammatory monocytes plays a causative role. Here we develop bioabsorbable poly-lactic/glycolic acid (PLGA) nanoparticles incorporating irbesartan, an angiotensin II type 1 receptor blocker with a peroxisome proliferator-activated receptor (PPAR)γ agonistic effect (irbesartan-NP). In a mouse model of IR injury, intravenous PLGA nanoparticles distribute to the IR myocardium and monocytes in the blood and in the IR heart. Single intravenous treatment at the time of reperfusion with irbesartan-NP (3.0 mg kg−1 irbesartan), but not with control nanoparticles or irbesartan solution (3.0 mg kg−1), inhibits the recruitment of inflammatory monocytes to the IR heart, and reduces the infarct size via PPARγ-dependent anti-inflammatory mechanisms, and ameliorates left ventricular remodeling 21 days after IR. Irbesartan-NP is a novel approach to treat myocardial IR injury in patients with AMI.

Myocardial ischemia-reperfusion (IR) injury limits the therapeutic effects of early reperfusion therapy for acute myocardial infarction (MI), in which mitochondrial permeability transition pore (mPTP) opening plays a critical role. Our aim was to determine whether poly-lactic/glycolic acid (PLGA) nanoparticle-mediated mitochondrial targeting of a molecule that inhibits mPTP opening, cyclosporine A (CsA), enhances CsA-induced cardioprotection. In an in vivo murine IR model, intravenously injected PLGA nanoparticles were located at the IR myocardium mitochondria. Treatment with nanoparticles incorporated with CsA (CsA-NP) at the onset of reperfusion enhanced cardioprotection against IR injury by CsA alone (as indicated by the reduced MI size at a lower CsA concentration) through the inhibition of mPTP opening. Left ventricular remodeling was ameliorated 28 days after IR, but the treatment did not affect inflammatory monocyte recruitment to the IR heart. In cultured rat cardiomyocytes in vitro, mitochondrial PLGA nanoparticle-targeting was observed after the addition of hydrogen peroxide, which represents oxidative stress during IR, and was prevented by CsA. CsA-NP can be developed as an effective mPTP opening inhibitor and may protect organs from IR injury.

Abstract-Pulmonary artery hypertension (PAH) is an intractable disease of the small PAs in which multiple pathogenic factors are involved. Statins are known to mitigate endothelial injury and inhibit vascular remodeling and inflammation, all of which play crucial roles in the pathogenesis of PAH. We tested the hypothesis that nanoparticle (NP)-mediated delivery of pitavastatin into the lungs can be a novel therapeutic approach for the treatment of PAH. Among the marketed statins, pitavastatin was found to have the most potent effects on proliferation of PA smooth muscle cells in vitro. We formulated pitavastatin-NP and found that pitavastatin-NP was more effective than pitavastatin alone in inhibiting cellular proliferation and inflammation in vitro. In a rat model of monocrotaline-induced PAH, a single intratracheal instillation of NP resulted in the delivery of NP into alveolar macrophages and small PAs for up to 14 days after instillation. Intratracheal treatment with pitavastatin-NP, but not with pitavastatin, attenuated the development of PAH and was associated with a reduction of inflammation and PA remodeling. NP-mediated pitavastatin delivery was more effective than systemic administration of pitavastatin in attenuating the development of PAH. Importantly, treatment with pitavastatin-NP 3 weeks after monocrotaline injection induced regression of PAH and improved survival rate. This mode of NP-mediated pitavastatin delivery into the lungs is effective in attenuating the development of PAH and inducing regression of established PAH, suggesting potential clinical significance for developing a new treatment for PAH. Key Words: pulmonary hypertension Ⅲ nanotechnology Ⅲ pitavastatin Ⅲ inflammation Ⅲ leukocytes P ulmonary artery hypertension (PAH) is an intractable disease of the small PAs resulting in progressive increases in pulmonary vascular resistance, right ventricular (RV) failure, and ultimately premature death. 1,2 Mortality from PAH remains high, even after introduction of vasodilator therapies such as prostacyclin infusion, endothelin receptor antagonists, and phosphodiesterase inhibitors (which have raised the 5-year survival rate to Ϸ50%). Although these drugs were originally developed for non-PAH vascular diseases, they were introduced into treatment for clinical PAH on the basis of the vasodilator hypothesis. Therefore, a new idea that might lead to a breakthrough curative treatment for PAH is urgently needed.In addition to vasoconstriction, other multiple factors (endothelial injury/apoptosis, obstructive vascular remodeling, proliferation, and inflammation) play an important role in the mechanism of PAH. 1,2 Therefore, we hypothesized that a controlled, local delivery system targeting a battery of those pathogenic factors intrinsic to PAH pathology would be a favorable therapeutic approach with high translational potential to clinical medicine. In this respect, we focused on the vasculoprotective effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, the so-called statins. Stati...

The pathophysiology of non-pulmonary vein (PV) triggers of atrial fibrillation (AF) is unclear. We hypothesized that left atrial non-PV (LANPV) triggers are associated with atrial tissue degeneration. This study analyzed 431 patients that underwent catheter ablation (mean age 62 yrs, 303 men, 255 paroxysmal AF [pAF] patients). Clinical and electrophysiological characteristics of non-PV trigger were analyzed. Fifty non-PV triggers in 40 patients (9.3%) were documented; LANPV triggers were the most prevalent (n = 19, 38%). LANPV triggers were correlated with non-paroxysmal AF (non-pAF) (OR 3.31, p = 0.04) whereas right atrial non-PV (RANPV) triggers (n = 14) and SVC triggers (n = 17) were not. The voltage at the LANPV sites during SR was 0.3 ± 0.16 mV (p < 0.001 vs. control site). Low-voltage areas (LVAs) in the LA were significantly greater in non-pAF compared to pAF (14.2% vs. 5.8%, p < 0.01). RANPV trigger sites had preserved voltage (0.74 ± 0.48 mV). Long-term outcomes of patients with non-PV triggers treated with tailored targeting strategies were not significantly inferior to those without non-PV triggers. In conclusion, non-PV triggers arise from the LA with degeneration, which may have an important role in AF persistence. A trigger-oriented, patient-tailored ablation strategy considering LA voltage map may be feasible and effective in persistent/recurrent AF.

Background The elevated D-dimer value is one of the clues used to diagnose acute aortic dissection (AAD), but the rapid D-dimer assay is not used at all emergency hospitals. The fibrinogen/fibrin degradation products (FDP) value is also an indicator of enhanced fibrinolysis and may therefore be a useful marker in patients with AAD. In addition, the association between FDP values and partial thrombosis of the false lumen is not elucidated. Patients The present study enrolled 50 patients (66.5±11.2 years of age; median, 66.5 years of age, male subjects comprised 60.0% of the series) with AAD who were admitted to the hospital between July 2005 and December 2007 and 57 patients with acute myocardial infarction (AMI; 70.8±10.4 years of age; median, 71.0 years of age, male subjects comprised 71.9% of the current series) served as a control group. Results The FDP values (μg/mL) in patients with AAD were significantly higher than those of AMI patients (40.2±78.6; median, 14.7 vs. 5.2±9.8; median, 1.7, p<0.001). A receiver operating characteristic curves analysis showed that an elevated FDP level (2.05 μg/mL) was predictive of a diagnosis of AAD with a sensitivity and specificity of 98% and 54%, respectively. The FDP levels of patients (n=14) who had partial thrombosis of the false lumen were significantly higher than in discharged patients without a surgical repair (n=21) who had a patent or complete thrombosis of the false lumen (35.8±43.2; median, 18.8 vs. 14.0±21.3; median, 5.5, p=0.01). Conclusion The measurement of FDP may therefore be useful for the initial assessment of patients with suspected AAD and in the prediction of thrombotic status of the false lumen.

Background The opening of mitochondrial permeability transition pore and inflammation cooperatively progress myocardial ischemia‐reperfusion (IR) injury, which hampers therapeutic effects of primary reperfusion therapy for acute myocardial infarction. We examined the therapeutic effects of nanoparticle‐mediated medicine that simultaneously targets mitochondrial permeability transition pore and inflammation during IR injury. Methods and Results We used mice lacking cyclophilin D (CypD, a key molecule for mitochondrial permeability transition pore opening) and C‐C chemokine receptor 2 and found that CypD contributes to the progression of myocardial IR injury at early time point (30–45 minutes) after reperfusion, whereas C‐C chemokine receptor 2 contributes to IR injury at later time point (45–60 minutes) after reperfusion. Double deficiency of CypD and C‐C chemokine receptor 2 enhanced cardioprotection compared with single deficiency regardless of the durations of ischemia. Deletion of C‐C chemokine receptor 2, but not deletion of CypD, decreased the recruitment of Ly‐6C high monocytes after myocardial IR injury. In CypD‐knockout mice, administration of interleukin‐1β blocking antibody reduced the recruitment of these monocytes. Combined administration of polymeric nanoparticles composed of poly‐lactic/glycolic acid and encapsulating nanoparticles containing cyclosporine A or pitavastatin, which inhibit mitochondrial permeability transition pore opening and monocyte‐mediated inflammation, respectively, augmented the cardioprotection as compared with single administration of nanoparticles containing cyclosporine A or pitavastatin after myocardial IR injury. Conclusions Nanoparticle‐mediated simultaneous targeting of mitochondrial injury and inflammation could be a novel therapeutic strategy for the treatment of myocardial IR injury.

A new series of layered selenides (LnO)CuSe (Ln=La, Ce, Nd, Sm, Gd, Tb, Dy, Ho, Y) with (LaO)AgS-type structure was prepared. All the compounds were semiconductors. Magnetic susceptibility measurements revealed that the lanthanide ions are in the trivalent state and the values of Weiss temperature θ lie within ±15 K for all the compounds. The preparation and the electrical resistivity of (LaO)Cu(S1-x Se x ) (0≤x≤1) and (La1-x Sr x )OCuSe (0≤x≤0.2) systems are also reported.