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Pulmonary regurgitation (PR) is a risk factor for sudden cardiac death in adult patients with repaired tetralogy of Fallot (TOF). However, transthoracic echocardiography (TTE) cannot fully visualize the pulmonary valve (PV) and PR. We investigated whether intracardiac echocardiography (ICE) could visualize the PV and PR better than TTE. Thirty adult patients with TOF (mean age 33 ± 15 years) scheduled for cardiac catheterization underwent ICE. The visualization of PV and the severity of PR were classified into three grades. ICE depicted the PV better than TTE (ICE vs. TTE: not visualized, partially visualized, and fully visualized: n = 1 [3%], n = 13 [43%], and n = 16 [53%] vs. n = 14 [47%], n = 13 [43%], and n = 3 [10%], p < 0.001). Especially in patients after pulmonary valve replacement (PVR), the PV was more fully visualized by ICE. The assessment of PR by TTE underestimated the severity of PR in comparison to cardiac magnetic resonance imaging (MRI) (severe PR: 8 [28%] vs. 22 [76%], p = 0.004), while there was no discrepancy between the results of ICE and MRI (21 [72%] vs. 22 [76%], p = 1.000). In comparison to TTE, ICE can safely provide better visualization of the PV and PR in adults with TOF, especially in patients who have undergone PVR.

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‐6Chigh 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.

BackgroundMitochondria‐mediated cell death plays a critical role in myocardial ischemia‐reperfusion (IR) injury. We hypothesized that nanoparticle‐mediated drug delivery of mitochondrial division inhibitor 1 (Mdivi1) protects hearts from IR injury through inhibition of mitochondria outer membrane permeabilization (MOMP), which causes mitochondrial‐mediated cell death. Methods and ResultsWe formulated poly (lactic‐co‐glycolic acid) nanoparticles containing Mdivi1 (Mdivi1‐NP). We recently demonstrated that these nanoparticles could be successfully delivered to the cytosol and mitochondria of cardiomyocytes under H2O2‐induced oxidative stress that mimicked IR injury. Pretreatment with Mdivi1‐NP ameliorated H2O2‐induced cell death in rat neonatal cardiomyocytes more potently than Mdivi1 alone, as indicated by a lower estimated half‐maximal effective concentration and greater maximal effect on cell survival. Mdivi1‐NP treatment of Langendorff‐perfused mouse hearts through the coronary arteries at the time of reperfusion reduced infarct size after IR injury more effectively than Mdivi1 alone. Mdivi1‐NP treatment also inhibited Drp1‐mediated Bax translocation to the mitochondria and subsequent cytochrome c leakage into the cytosol, namely, MOMP, in mouse IR hearts. MOMP inhibition was also observed in cyclophilin D knockout (CypD‐KO) mice, which lack the mitochondrial permeability transition pore (MPTP) opening. Intravenous Mdivi1‐NP treatment in vivo at the time of reperfusion reduced IR injury in wild‐type and CypD‐KO mice, but not Bax‐KO mice. ConclusionsMdivi1‐NP treatment reduced IR injury through inhibition of MOMP, even in the absence of a CypD/MPTP opening. Thus, nanoparticle‐mediated drug delivery of Mdivi1 may be a novel treatment strategy for IR injury.