Nanoparticle-mediated targeting of pioglitazone to inflammatory monocytes protected the heart from IR injury and cardiac remodeling by antagonizing monocyte/macrophage-mediated acute inflammation and promoting cardiac healing after AMI.

No abstract

A 77-year-old man was referred to our cardiovascular department for detailed examination after abnormal electrocardiography findings were obtained during a preoperative cataract surgery workup. Ultrasound echocardiography (UCG) and computed tomography (CT) revealed evidence of previous myocardial infarction with anteroseptal akinesis and a left ventricular (LV) thrombus (14 × 12 mm). Dabigatran (220 mg/day) was prescribed as an outpatient treatment, and the disappearance of the LV thrombus was confirmed by UCG and CT 27 days after dabigatran initiation. No thromboembolism occurred between treatment initiation and thrombus resolution. Our results indicate that dabigatran has thrombolytic action on an acute pre-existing intracardiac thrombus.

Ischemia-reperfusion injury impairs the efficacy of reperfusion therapy after ischemic stroke. cyclophilin D (cypD)-mediated openings of mitochondrial permeability transition pore (mptp) and subsequent monocyte-mediated inflammation are considered as major mechanisms of reperfusion injury. However, no medical therapies are currently available. Therefore, we have tested a hypothesis that simultaneous targeting of mPTP and inflammation confers substantial neuroprotection after cerebral ischemia-reperfusion. To address this point, we prepared CypD knockout mice, CC chemokine receptor 2 (CCR2) knockout mice and CypD/CCR2 double knockout mice. These mice were subjected to 60 min transient cerebral ischemia by occluding middle cerebral arteries. Neurological deficits evaluated 3 days after reperfusion were significantly attenuated in CypD/CCR2 double knockout mice as compared to wild-type mice and other single knockout mice. Then, we have prepared polymeric nanoparticles containing cyclosporine A (CsA-NPs) and pitavastatin (Pitava-NPs), targeting mPTP opening and inflammation, respectively. Simultaneous administration of CsA-NP and Pitava-NP at the time of reperfusion also decreased infarct size and attenuated neurological deficits as compared to control nanoparticles and single administration of CsA-NPs or Pitava-NPs. These results indicate that simultaneous targeting of the mPTP opening and monocyte-mediated inflammation could be a novel strategy for better neurological outcomes in patients with ischemic stroke. Innovative therapeutic strategies for protecting the brain from ischemia-reperfusion (IR) injury are necessary to decrease infarct volume and improve clinical outcomes after reperfusion therapy for the treatment of ischemic stroke 1 .Within several minutes after reperfusion, opening of mitochondrial permeability transition pore (mPTP) triggers cell deaths in tissues exposed to IR injury 2. Inflammatory monocytes, Ly6C high CCR2 + in mice or CD14 high CD16 − in humans, accumulate to the cerebral tissue as early as several hours after reperfusion and also trigger cell death 3-8. Cyclosporine A (CsA) is a widely used drug after organ transplantation which binds to cyclophilin A and inhibits calcineurin activities in T cells, and thus exerts immunosuppressive effects. CsA also binds to cyclophilin D (CypD), which results in inhibition of mPTP opening and subsequent cell deaths 9. In experimental animals, intravenous administered CsA decreases infarct size 10. In clinical trials, however, intravenously administered CsA (2.0 mg/kg) failed to improve neurological outcomes after ischemic stroke 11 .This discrepancy raises at least two possibilities. First, monotherapy targeting only mPTP was insufficient in humans. Second, drug delivery to target organ was insufficient. In this study, we prepared mice lacking both CypD and CCR2 to elucidate whether targeting two mechanisms, i.e. mPTP opening and inflammation, confers substantial neuroprotection as evidenced by

Hyperuricemia is related to an increased risk of cardiovascular events from a meta-analysis and antihyperuricemia agents may influence to cardiac function. We evaluated the effect of febuxostat on echocardiographic parameters of diastolic function in patients with asymptomatic hyperuricemia as a prespecified endpoint in the subanalysis of the PRIZE study. Patients in the PRIZE study were assigned randomly to either add-on febuxostat treatment group or control group with only appropriate lifestyle modification. Of the 514 patients in the overall study, 65 patients (31 in the febuxostat group and 34 in the control group) who had complete follow-up echocardiographic data of the ratio of peak early diastolic transmitral flow velocity (E) to peak early diastolic mitral annular velocity (e′) at baseline and after 12 and 24 months were included. The primary endpoint was a comparison of the changes in the E/e′ between the two groups from baseline to 24 months. Interestingly, e′ was slightly decreased in the control group compared with in the febuxostat group (treatment p = 0.068, time, p = 0.337, treatment × Time, p = 0.217). As a result, there were significant increases in E/e′ (treatment p = 0.045, time, p = 0.177, treatment × time, p = 0.137) after 24 months in the control group compared with the febuxostat group. There was no significant difference in the serum levels of N-terminal-pro brain natriuretic peptide and high-sensitive troponin I between the two groups during the study period. In conclusions, additional febuxostat treatment in patients with asymptomatic hyperuricemia for 24 months might have a potential of preventable effects on the impaired diastolic dysfunction.