Yoshihiro Asano

Dipeptidyl-peptidase IV inhibition improves pathophysiology of heart failure and increases survival rate in pressure-overloaded mice

Incretin hormones, including glucagon-like peptide-1 (GLP-1), a target for diabetes mellitus (DM) treatment, are associated with cardioprotection. As dipeptidyl-peptidase IV (DPP-IV) inhibition increases plasma GLP-1 levels in vivo, we investigated the cardioprotective effects of the DPP-IV inhibitor vildagliptin in a murine heart failure (HF) model. We induced transverse aortic constriction (TAC) in C57BL/6J mice, simulating pressure-overloaded cardiac hypertrophy and HF. TAC or sham-operated mice were treated with or without vildagliptin. An intraperitoneal glucose tolerance test revealed that blood glucose levels were higher in the TAC than in sham-operated mice, and these levels improved with vildagliptin administration in both groups. Vildagliptin increased plasma GLP-1 levels in the TAC mice and ameliorated TAC-induced left ventricular enlargement and dysfunction. Vildagliptin palliated both myocardial apoptosis and fibrosis in TAC mice, demonstrated by histological, gene and protein expression analyses, and improved survival rate on day 28 (TAC with vildagliptin, 67.5%; TAC without vildagliptin, 41.5%; P < 0.05). Vildagliptin improved cardiac dysfunction and overall survival in the TAC mice, both by improving impaired glucose tolerance and by increasing GLP-1 levels. DPP-IV inhibitors represent a candidate treatment for HF patients with or without DM.

Augmented AMPK activity inhibits cell migration by phosphorylating the novel substrate Pdlim5

Augmented AMP-activated protein kinase (AMPK) activity inhibits cell migration, possibly contributing to the clinical benefits of chemical AMPK activators in preventing atherosclerosis, vascular remodelling and cancer metastasis. However, the underlying mechanisms remain largely unknown. Here we identify PDZ and LIM domain 5 (Pdlim5) as a novel AMPK substrate and show that it plays a critical role in the inhibition of cell migration. AMPK directly phosphorylates Pdlim5 at Ser177. Exogenous expression of phosphomimetic S177D-Pdlim5 inhibits cell migration and attenuates lamellipodia formation. Consistent with this observation, S177D-Pdlim5 suppresses Rac1 activity at the cell periphery and displaces the Arp2/3 complex from the leading edge. Notably, S177D-Pdlim5, but not WT-Pdlim5, attenuates the association with Rac1-specific guanine nucleotide exchange factors at the cell periphery. Taken together, our findings indicate that phosphorylation of Pdlim5 on Ser177 by AMPK mediates inhibition of cell migration by suppressing the Rac1-Arp2/3 signalling pathway.

H 2 Mediates Cardioprotection Via Involvements of K ATP Channels and Permeability Transition Pores of Mitochondria in Dogs

PurposeInhalation of hydrogen (H2) gas has been shown to limit infarct size following ischemia-reperfusion injury in rat hearts. However, H2 gas-induced cardioprotection has not been tested in large animals and the precise cellular mechanism of protection has not been elucidated. We investigated whether opening of mitochondrial ATP-sensitive K+ channels (mKATP) and subsequent inhibition of mitochondrial permeability transition pores (mPTP) mediates the infarct size-limiting effect of H2 gas in canine hearts.MethodsThe left anterior descending coronary artery of beagle dogs was occluded for 90xa0min followed by reperfusion for 6xa0h. Either 1.3% H2 or control gas was inhaled from 10xa0min prior to start of reperfusion until 1xa0h of reperfusion, in the presence or absence of either 5-hydroxydecanoate (5-HD; a selective mKATP blocker), or atractyloside (Atr; a mPTP opener).ResultsSystemic hemodynamic parameters did not differ among the groups. Nevertheless, H2 gas inhalation reduced infarct size normalized by risk area (20.6u2009±u20092.8% vs. control gas 44.0u2009±u20092.0%; pu2009<u20090.001), and administration of either 5-HD or Atr abolished the infarct size-limiting effect of H2 gas (42.0u2009±u20092.2% with 5-HD and 45.1u2009±u20092.7% with Atr; both pu2009<u20090.001 vs. H2 group). Neither Atr nor 5-HD affected infarct size per se. Among all groups, NAD content and the number of apoptotic and 8-OHdG positive cells was not significantly different, indicating that the cardioprotection afforded by H2 was not due to anti-oxidative actions or effects on the NADH dehydrogenase pathway.ConclusionsInhalation of H2 gas reduces infarct size in canine hearts via opening of mitochondrial KATP channels followed by inhibition of mPTP. H2 gas may provide an effective adjunct strategy in patients with acute myocardial infarction receiving reperfusion therapy.

Usefulness of transient elastography for noninvasive and reliable estimation of right-sided filling pressure in heart failure.

Accurate noninvasive assessment of right atrial pressure (RAP) is important for volume management in patients with heart failure (HF). Transient elastography is a noninvasive and reliable method to assess liver stiffness (LS). We investigated the value of LS for evaluation of RAP in patients with HF without structural liver disease. We measured LS using transient elastography (Fibroscan) in 31 patients undergoing right-sided cardiac catheterization (test group). The relation between LS and RAP found in the test group was used to derive the best-fit model to predict RAP. The applicability of the model was then tested in a validation group of 49 additional patients. There was an excellent correlation between LS and RAP in the test group (r = 0.95, p <0.0001; RAP = -5.8 + 6.7 × ln [LS]). Natural log transformation (ln) of LS provided the regression equation to predict RAP. When the equation model derived from the test group was applied to the validation group, predicted RAP correlated excellently with actual RAP (r = 0.90, p <0.0001). The receiver operating characteristic curve analyses in the test group showed that LS favorably compared with echocardiography for detecting RAP >10 mm Hg (area under the curve 0.958 vs 0.800, respectively, p = 0.047). In the validation group, LS with a cut-off value of 10.6 kPa for identifying RAP >10 mm Hg had a higher sensitivity and accuracy (p = 0.046 and p = 0.049, respectively) than echocardiography. In conclusion, LS may offer an accurate noninvasive diagnostic method to assess RAP in patients with HF.

Liposomal Amiodarone Augments Anti-arrhythmic Effects and Reduces Hemodynamic Adverse Effects in an Ischemia/ Reperfusion Rat Model

PurposeAlthough amiodarone is recognized as the most effective anti-arrhythmic drug available, it has negative hemodynamic effects. Nano-sized liposomes can accumulate in and selectively deliver drugs to ischemic/reperfused (I/R) myocardium, which may augment drug effects and reduce side effects. We investigated the effects of liposomal amiodarone on lethal arrhythmias and hemodynamic parameters in an ischemia/reperfusion rat model.Methods and ResultsWe prepared liposomal amiodarone (mean diameter: 113u2009±u20098xa0nm) by a thin-film method. The left coronary artery of experimental rats was occluded for 5xa0min followed by reperfusion. Ex vivo fluorescent imaging revealed that intravenously administered fluorescent-labeled nano-sized beads accumulated in the I/R myocardium. Amiodarone was measurable in samples from the I/R myocardium when liposomal amiodarone, but not amiodarone, was administered. Although the intravenous administration of amiodarone (3xa0mg/kg) or liposomal amiodarone (3xa0mg/kg) reduced heart rate and systolic blood pressure compared with saline, the decrease in heart rate or systolic blood pressure caused by liposomal amiodarone was smaller compared with a corresponding dose of free amiodarone. The intravenous administration of liposomal amiodarone (3xa0mg/kg), but not free amiodarone (3xa0mg/kg), 5xa0min before ischemia showed a significantly reduced duration of lethal arrhythmias (18u2009±u20099xa0s) and mortality (0xa0%) during the reperfusion period compared with saline (195u2009±u200942xa0s, 71xa0%, respectively).ConclusionsTargeting the delivery of liposomal amiodarone to ischemic/reperfused myocardium reduces the mortality due to lethal arrhythmia and the negative hemodynamic changes caused by amiodarone. Nano-size liposomes may be a promising drug delivery system for targeting I/R myocardium with cardioprotective agents.

Comprehensive metagenomic approach for detecting causative microorganisms in culture-negative infective endocarditis

Comprehensive metagenomic approach for detecting causative microorganisms in culture-negative infective endocarditis Atsuko Imai , Kazuyoshi Gotoh , Yoshihiro Asano ⁎, Noriaki Yamada , Daisuke Motooka , Masaki Fukushima , Machiko Kanzaki , Tomohito Ohtani , Yasushi Sakata , Hiroyuki Nishi , Koichi Toda , Yoshiki Sawa , Issei Komuro , Toshihiro Horii , Tetsuya Iida , Shota Nakamura , Seiji Takashima a,d

Carperitide induces coronary vasodilation and limits infarct size in canine ischemic hearts: role of NO.

Carperitide is effective for heart failure (HF) owing to its diuretic and vasodilatory effects. This recombinant peptide may also have direct cardioprotective effects because carperitide reduces the severity of heart failure and limits infarct size. Because coronary vasodilation is an important cardioprotective treatment modality, we investigated whether carperitide increased coronary blood flow (CBF) and improved myocardial metabolic and contractile dysfunction during ischemia in canine hearts. We also tested whether carperitide is directly responsible for limiting the infarct size. We infused carperitide at 0.025–0.2u2009μgu2009kg−1u2009min−1 into the canine coronary artery. A minimum dose of 0.1u2009μgu2009kg−1u2009min−1 was required to obtain maximal vasodilation. To test the effects of carperitide on ischemic hearts, we reduced perfusion pressure in the left anterior descending coronary artery such that CBF decreased to one-third of the baseline value. At 10u2009min after carperitide was infused at a dose of 0.1u2009μgu2009kg−1u2009min−1, we observed increases in CBF, fractional shortening (FS) and pH levels in coronary venous blood without concomitant increases in cardiac nitric oxide (NO) levels; these changes were attenuated using either the atrial natriuretic peptide receptor antagonist HS-142-1 or the NO synthase inhibitor Lω-nitroarginine methyl ester (L-NAME). Cyclic guanosine monophosphate (GMP) levels in the coronary artery were elevated in response to carperitide that also limited the infarct size after 90u2009min of ischemia and subsequent reperfusion. Again, these effects were blunted by L-NAME. Carperitide increases CBF, reduces myocardial contractile and metabolic dysfunction and limits infarct size. In addition, NO is necessary for carperitide-induced vasodilation and cardioprotection in ischemic hearts.

Noninvasive and quantitative live imaging reveals a potential stress-responsive enhancer in the failing heart

Recent advances in genome analysis have enabled the identification of numerous distal enhancers that regulate gene expression in various conditions. However, the enhancers involved in pathological conditions are largely unknown because of the lack of in vivo quantitative assessment of enhancer activity in live animals. Here, we established a noninvasive and quantitative live imaging system for monitoring transcriptional activity and identified a novel stress‐responsive enhancer of Nppa and Nppb, the most common markers of heart failure. The enhancer is a 650‐bp fragment within 50 kb of the Nppa and Nppb loci. A chromosome conformation capture (3C) assay revealed that this distal enhancer directly interacts with the 5‐flanking regions of Nppa and Nppb. To monitor the enhancer activity in a live heart, we established an imaging system using the firefly luciferase reporter. Using this imaging system, we observed that the novel enhancer activated the reporter gene in pressure overload‐induced failing hearts (failing hearts: 5.7±1.3‐fold; sham‐surgery hearts: 1.0±0.2‐fold; P<0.001, repeated‐measures ANOVA). This method will be particularly useful for identifying enhancers that function only during pathological conditions.—Matsuoka, K., Asano, Y., Higo, S., Tsukamoto, O., Yan, Y., Yamazaki, S., Matsuzaki, T., Kioka, H., Kato, H., Uno, Y., Asakura, M., Asanuma, H., Minamino, T., Aburatani, H., Kitakaze, M., Komuro, I., and Takashima, S. Noninvasive and quantitative live imaging reveals a potential stress‐responsive enhancer in the failing heart. FASEB J. 28, 1870–1879 (2014). www.fasebj.org

Switching from carvedilol to bisoprolol ameliorates adverse effects in heart failure patients with dizziness or hypotension

BACKGROUNDnTreatment with carvedilol is an established primary therapy for patients with heart failure (HF). However, its most common adverse effects, dizziness and hypotension, often discourage continuation or dosage increase. The aim of this study was to examine whether switching to bisoprolol from carvedilol would help to avoid adverse symptoms and signs related to carvedilol administration.nnnMETHODS AND SUBJECTSnData were retrospectively collected from 23 patients with HF [age 57±18 years, left ventricular ejection fraction (LVEF) 33±15%] who could not increase the dosage of carvedilol because of dizziness or hypotension, defined as systolic blood pressure<90 mmHg. Before and immediately after, and 6 months after switching to bisoprolol, we examined symptoms, vital signs, laboratory data, and New York Heart Association functional class. Furthermore, left ventricular (LV) dimension and ejection fraction (EF) were evaluated in 19 patients using echocardiography.nnnRESULTSnAll 13 patients with dizziness (100%) and 9 of 16 with hypotension (56%) were relieved of adverse symptoms or signs. The mean dose of carvedilol before switching was 5.60±3.43 mg. Immediately after the switch, the mean dose of bisoprolol was 1.84±1.08 mg and then increased to 3.13±1.74 mg after 6 months (p<0.01). At 6-month follow-up examinations, LV function determined by LVEF was significantly improved, which was accompanied by increased exercise tolerance.nnnCONCLUSIONnSwitching from carvedilol to bisoprolol may help with continuation of β-blocker treatment as well as dosage increase in HF patients with adverse symptoms or signs, allowing them to reach the target dose.