Search

Anserine, an imidazole dipeptide, is present in the muscles of birds and fish and has various bioactivities, such as anti-inflammatory and anti-fatigue effects. However, the effect of anserine on the development of heart failure remains unknown. We cultured primary cardiomyocytes with 0.03 mM to 10 mM anserine and stimulated them with phenylephrine for 48 h. Anserine significantly suppressed the phenylephrine-induced increases in cardiomyocyte hypertrophy, ANF and BNP mRNA levels, and histone H3K9 acetylation. An in vitro histone acetyltransferase (HAT) assay showed that anserine directly suppressed p300-HAT activity with an IC 50 of 1.87 mM. Subsequently, 8-week-old male C57BL/6J mice were subjected to transverse aortic constriction (TAC) and were randomly assigned to receive daily oral treatment with anserine-containing material, Marine Active ® (60 or 200 mg/kg anserine) or vehicle for 8 weeks. Echocardiography revealed that anserine 200 mg/kg significantly prevented the TAC-induced increase in left ventricular posterior wall thickness and the decrease in left ventricular fractional shortening. Moreover, anserine significantly suppressed the TAC-induced acetylation of histone H3K9. These results indicate that anserine suppresses TAC-induced systolic dysfunction, at least in part, by inhibiting p300-HAT activity. Anserine may be used as a pharmacological agent for human heart failure therapy.

Aims: As heart failure (HF) progresses, ATP levels in myocardial cells decrease, and myocardial contractility also decreases. Inotropic drugs improve myocardial contractility but increase ATP consumption, leading to poor prognosis. Kyoto University Substance 121 (KUS121) is known to selectively inhibit the ATPase activity of valosin-containing protein, maintain cellular ATP levels, and manifest cytoprotective effects in several pathological conditions. The aim of this study is to determine the therapeutic effect of KUS121 on HF models., Methods and Results: Cultured cell, mouse, and canine models of HF were used to examine the therapeutic effects of KUS121. The mechanism of action of KUS121 was also examined. Administration of KUS121 to a transverse aortic constriction (TAC)-induced mouse model of HF rapidly improved the left ventricular ejection fraction and improved the creatine phosphate/ATP ratio. In a canine model of high frequency-paced HF, administration of KUS121 also improved left ventricular contractility and decreased left ventricular end-diastolic pressure without increasing the heart rate. Long-term administration of KUS121 to a TAC-induced mouse model of HF suppressed cardiac hypertrophy and fibrosis. In H9C2 cells, KUS121 reduced ER stress. Finally, in experiments using primary cultured cardiomyocytes, KUS121 improved contractility and diastolic capacity without changing peak Ca 2+ levels or contraction time. These effects were not accompanied by an increase in cyclic adenosine monophosphate or phosphorylation of phospholamban and ryanodine receptors., Conclusions: KUS121 ameliorated HF by a mechanism totally different from that of conventional catecholamines. We propose that KUS121 is a promising new option for the treatment of HF., Competing Interests: Declaration of Competing Interest In relation to this manuscript, Kyoto University has applied for a patent (Tokugan 2021–211106), and S.T., C.O., T.H., S.W., A.K., and K.O. are named as inventors on the patent. The other authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Aims: Previous studies have shown that proteinuria is independently associated with the incidence of atrial fibrillation (AF), and is also associated with the incidence of cardiovascular events such as stroke and thromboembolism in patients with AF. However, the association of proteinuria with heart failure (HF) events in patients with AF remains unclear., Methods and Results: The Fushimi AF Registry is a community-based prospective study of patients with AF. Of the entire cohort of 4489 patients, 2164 patients had available data of proteinuria. We compared the clinical background and outcomes between patients with proteinuria (n = 606, 28.0%) and those without (n = 1558, 72.0%). Patients with proteinuria were older and had a higher prevalence of major co-morbidities. During the median follow-up of 5.0 years, the incidence rates of HF events (composite of cardiac death or HF hospitalization) were higher in patients with proteinuria than those without (4.1% vs. 2.1% person-year, P < 0.01). Multivariate analyses revealed that proteinuria was an independent risk factor of the incidence of HF events [adjusted hazard ratio (HR): 1.40, 95% confidence interval (CI): 1.13-1.74]. This association was consistent among the various subgroups, except for the age subgroup in which there was a significant interaction (P < 0.01) between younger (<75 years) (unadjusted HR: 3.03, 95% CI: 2.12-4.34) and older (≥75 years) patients (unadjusted HR: 1.59, 95% CI: 1.23-2.05)., Conclusion: Our community-based large prospective cohort suggests that proteinuria is independently associated with the incidence of HF events in Japanese patients with AF., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: Atrial fibrillation (AF) increases the risk of heart failure (HF); however, little focus has been placed on the prevention of HF in patients with AF. Left ventricular ejection fraction (LVEF) is an established echocardiographic parameter in HF patients. We sought to investigate the association of LVEF with HF events in AF patients without pre-existing HF., Methods and Results: The Fushimi AF Registry is a community-based prospective survey of AF patients in Fushimi-ku, Japan. In this analysis, we excluded patients with pre-existing HF (defined as having one of the following: prior HF hospitalization, New York Heart Association class ≥ 2 in association with heart disease, or LVEF < 40%). Among 3233 AF patients without pre-existing HF, we investigated 2459 patients with the data of LVEF at enrolment. We divided the patients into three groups stratified by LVEF [mildly reduced LVEF (40-49%), below normal LVEF (50-59%), and normal LVEF (≥60%)] and compared the backgrounds and incidence of HF hospitalization between the groups. Of 2459 patients [mean age: 72.4 ± 10.5 years, female: 917 (37%), paroxysmal AF: 1405 (57%), and mean CHA 2 DS 2 -VASc score: 3.0 ± 1.6], the mean LVEF was 66 ± 8% [mildly reduced LVEF: 114 patients (5%), below normal LVEF: 300 patients (12%), and normal LVEF: 2045 patients (83%)]. Patients with lower LVEF demonstrated lower prevalence of female and paroxysmal AF (both P < 0.01), but age and CHA 2 DS 2 -VASc score were comparable between the three groups (both P > 0.05). During the median follow-up period of 6.0 years, 255 patients (10%) were hospitalized for HF (annual incidence: 1.9% per person-year). Multivariable Cox regression analysis demonstrated that lower LVEF strata were independently associated with the risk of HF [mildly reduced LVEF (40-49%): hazard ratio = 2.98, 95% confidence interval = 1.99-4.45 and below normal LVEF (50-59%): hazard ratio = 2.01, 95% confidence interval = 1.44-2.82, compared with normal LVEF (≥60%)] after adjustment by age, sex, type of AF, and CHA 2 DS 2 -VASc score. LVEF < 60% was significantly associated with the higher risk of HF hospitalization across all major subgroups without significant interaction (P for interaction; all P > 0.05). LVEF had an independent and incremental prognostic value for HF hospitalization in addition to natriuretic peptide levels in AF patients without pre-existing HF., Conclusions: Lower LVEF was significantly associated with the higher incidence of HF hospitalization in AF patients without pre-existing HF, leading to the future risk stratification for and prevention of incident HF in AF patients., (© 2023 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Hypertrophic stress-induced cardiac remodeling is a compensatory mechanism associated with cardiomyocyte hypertrophy and cardiac fibrosis. Continuation of this response eventually leads to heart failure. The histone acetyltransferase p300 plays an important role in the development of heart failure, and may be a target for heart failure therapy. The phenolic phytochemical 6-shogaol, a pungent component of raw ginger, has various bioactive effects; however, its effect on cardiovascular diseases has not been investigated. One micromolar of 6-shogaol suppressed phenylephrine (PE)-induced increases in cardiomyocyte hypertrophy in rat primary cultured cardiomyocytes. In rat primary cultured cardiac fibroblasts, 6-shogaol suppressed transforming growth factor-beta (TGF-β)-induced increases in L-proline incorporation. It also blocked PE- and TGF-β-induced increases in histone H3K9 acetylation in the same cells and in vitro. An in vitro p300-HAT assay revealed that 6-shogaol suppressed histone acetylation. The mice underwent transverse aortic constriction (TAC) surgery, and were administered 0.2 or 1 mg/kg of 6-shogaol daily for 8 weeks. 6-shogaol prevented TAC-induced systolic dysfunction and cardiac hypertrophy in a dose-dependent manner. Furthermore, it also significantly inhibited TAC-induced increases in histone H3K9 acetylation. These results suggest that 6-shogaol may ameliorate heart failure through a variety of mechanisms, including the inhibition of p300-HAT activity.

Background: Auraptene derived from the peel of Citrus hassaku possesses anti-tumor, anti-inflammatory, and neuroprotective activities. Thus, it could be a valuable pharmacological alternative to treat some diseases. However, the therapeutic value of auraptene for heart failure (HF) is unknown., Study Design/methods: In cultured cardiomyocytes from neonatal rats, the effect of auraptene on phenylephrine-induced hypertrophic responses and peroxisome proliferator-activated receptor-alpha (PPARα)-dependent gene transcriptions. To investigate whether auraptene prevents the development of heart failure after myocardial infarction (MI) in vivo, Sprague-Dawley rats with moderate MI (fractional shortening < 40%) were randomly assigned for treatment with low- or high-dose auraptene (5 or 50 mg/kg/day, respectively) or vehicle for 6 weeks. The effects of auraptene were evaluated by echocardiography, histological analysis, and the measurement of mRNA levels of hypertrophy, fibrosis, and PPARα-associated genes., Results: In cultured cardiomyocytes, auraptene repressed phenylephrine-induced hypertrophic responses, such as increases in cell size and activities of atrial natriuretic factor and endothelin-1 promoters. Auraptene induced PPARα-dependent gene activation by enhancing cardiomyocyte peroxisome proliferator-responsive element reporter activity. The inhibition of PPARα abrogated the protective effect of auraptene on phenylephrine-induced hypertrophic responses. In rats with MI, auraptene significantly improved MI-induced systolic dysfunction and increased posterior wall thickness compared to the vehicle. Auraptene treatment also suppressed MI-induced increases in myocardial cell diameter, perivascular fibrosis, and expression of hypertrophy and fibrosis response markers at the mRNA level compared with vehicle treatment. MI-induced decreases in the expression of PPARα-dependent genes were improved by auraptene treatment., Conclusions: Auraptene has beneficial effects on MI-induced cardiac hypertrophy and left ventricular systolic dysfunction in rats, at least partly due to PPARα activation. Further clinical studies are required to evaluate the efficacy of auraptene in patients with HF., Competing Interests: Declaration of Competing Interest None., (Copyright © 2022. Published by Elsevier GmbH.)

While the cardioprotective functions of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and omega-3 unsaturated fatty acids have been previously demonstrated, little is known about their effects on cardiomyocyte hypertrophy. In this study, we compared the effects of EPA and DHA on hypertrophic responses in cardiomyocytes and development of heart failure in rats with myocardial infarction (MI). Both EPA and DHA significantly suppressed phenylephrine- and p300-induced cardiomyocyte hypertrophy, transcription of hypertrophy response genes, and acetylation of histone H3K9 in cardiomyocytes. EPA and DHA directly inhibited p300-histone acetyltransferase activity (IC50: 37.8 and 30.6 μM, respectively). Further, EPA- and DHA-induced allosteric inhibition of histones and competitive inhibition of acetyl-CoA, and significantly prevented p300-induced hypertrophic responses. Rats with moderate MI (left ventricular fractional shortening [FS] <40%) were randomly assigned to three groups, namely, vehicle (saline), EPA (1 g/kg), and DHA (1 g/kg). One week after the operation, rats were orally administrated with test agents for 6 weeks. Echocardiographic analysis demonstrated that both EPA and DHA treatments preserved FS and prevented MI-induced left ventricular remodeling. Furthermore, EPA and DHA significantly suppressed the MI-induced increase in myocardial cell diameter, perivascular fibrosis, mRNA levels of hypertrophic markers, fibrosis, and acetylation of histone H3K9. The effects on hypertrophic responses and the development of heart failure were not different between EPA and DHA groups. Both EPA and DHA suppressed hypertrophic responses and the development of heart failure to the same extent through the inhibition of p300-HAT activity., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Ecklonia stolonifera Okamura extract (ESE) has been reported to have various bioactive effects, but its effects on cardiovascular disease have not yet been investigated. First, primary neonatal rat cultured cardiomyocytes were treated with ESE and stimulated with phenylephrine (PE) for 48 h. ESE (1000 µg/mL) significantly suppressed PE-induced cardiomyocyte hypertrophy, hypertrophy-related gene transcription, and the acetylation of histone H3K9. An in vitro p300-HAT assay indicated that ESE directly inhibited p300-HAT activity. Next, one week after myocardial infarction (MI) surgery, rats (left ventricular fractional shortening (LVFS) < 40%) were randomly assigned to three groups: vehicle (saline, n = 9), ESE (0.3 g/kg, n = 10), or ESE (1 g/kg, n = 10). Daily oral administration was carried out for 8 weeks. After treatment, LVFS was significantly higher in the ESE (1 g/kg) group than in the vehicle group. The ESE treatments also significantly suppressed MI-induced increases in myocardial cell diameter, perivascular fibrosis, hypertrophy- and fibrosis-related gene transcription, and the acetylation of histone H3K9. These results suggest that ESE suppressed both hypertrophic responses in cardiomyocytes and the development of heart failure in rats by inhibiting p300-HAT activity. Thus, this dietary extract is a potential novel therapeutic strategy for heart failure in humans.

The activation of the GATA-binding factor 4 (GATA4) transcription factor induces cardiac hypertrophy and heart failure. The multimerization of transcription factors often plays an important role in the regulation of transcriptional activity. Here, we report that the GATA4 transcription factor forms a homomultimer and that residues 308-326 of GATA4 are necessary for its multimerization. The acetylation of GATA4 by the transcriptional co-activator p300 induces the multimerization of GATA4 and activates its DNA binding activity. In addition, we found that the suppression of GATA4 multimerization did not reduce its acetylation, but repressed GATA4/p300-induced gene transcription. Furthermore, the inhibition of GATA4 multimerization suppressed phenylephrine (PE)-induced hypertrophic response in cardiomyocytes. This study demonstrates that the multimerization of GATA4 during the p300-induced acetylation of GATA4 activates the transcription of hypertrophic response genes, which leads to cardiomyocyte hypertrophy. Therefore, the inhibition of GATA4 homomultimerization could serve as a potential therapeutic strategy for the development of novel drugs against heart failure., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Aims: Endothelial cell vascular endothelial growth factor receptor 2 (VEGFR-2) plays a pivotal role in angiogenesis, which induces physiological cardiomyocyte hypertrophy via paracrine signalling between endothelial cells and cardiomyocytes. We investigated whether a decrease in circulating soluble VEGFR-2 (sVEGFR-2) levels is associated with poor prognosis in patients with chronic heart failure (HF)., Methods and Results: We performed a multicentre prospective cohort study of 1024 consecutive patients with HF, who were admitted to hospitals due to acute decompensated HF and were stabilized after initial management. Serum levels of sVEGFR-2 were measured at discharge. Patients were followed up over 2 years. The outcomes were cardiovascular death, all-cause death, major adverse cardiovascular events (MACE) defined as a composite of cardiovascular death and HF hospitalization, and HF hospitalization. The mean age of the patients was 75.5 (standard deviation, 12.6) years, and 57% were male. Patients with lower sVEGFR-2 levels were older and more likely to be female, and had greater proportions of atrial fibrillation and anaemia, and lower proportions of diabetes, dyslipidaemia, and HF with reduced ejection fraction (<40%). During the follow-up, 113 cardiovascular deaths, 211 all-cause deaths, 350 MACE, and 309 HF hospitalizations occurred. After adjustment for potential clinical confounders and established biomarkers [N-terminal B-type natriuretic peptide (NT-proBNP), high-sensitivity cardiac troponin I, and high-sensitivity C-reactive protein], a low sVEGFR-2 level below the 25th percentile was significantly associated with cardiovascular death [hazard ratio (HR), 1.79; 95% confidence interval (CI), 1.16-2.74] and all-cause death (HR, 1.43; 95% CI, 1.04-1.94), but not with MACE (HR, 1.11; 95% CI, 0.86-1.43) or HF hospitalization (HR, 1.03; 95% CI, 0.78-1.35). The stratified analyses revealed that a low sVEGFR-2 level below the 25th percentile was significantly associated with cardiovascular death (HR, 1.76; 95% CI, 1.07-2.85) and all-cause death (HR, 1.49; 95% CI, 1.03-2.15) in the high-NT-proBNP group (above the median), but not in the low-NT-proBNP group. Notably, the patients with high-NT-proBNP and low-sVEGFR-2 (below the 25th percentile) had a 2.96-fold higher risk (95% CI, 1.56-5.85) for cardiovascular death and a 2.40-fold higher risk (95% CI, 1.52-3.83) for all-cause death compared with those with low-NT-proBNP and high-sVEGFR-2., Conclusions: A low sVEGFR-2 value was independently associated with cardiovascular death and all-cause death in patients with chronic HF. These associations were pronounced in those with high NT-proBNP levels., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: The impact of catheter ablation (CA) on the long-term clinical outcomes in atrial fibrillation (AF) are unclear due to limited cohort investigations., Methods: The Fushimi AF Registry is a community-based prospective survey of patients with AF in Fushimi-ku, Kyoto, Japan. Of 4465 patients enrolled between March 2011 and July 2019, analyses were performed on 2639 patients (492 patients who underwent CA and 2147 patients who received standard rhythm- and/or rate-control drug therapy at baseline). We compared the baseline characteristics and the incidence of major adverse cardiovascular events (MACE: the composite of cardiovascular death, heart failure hospitalization, myocardial infarction, ischemic stroke or systemic embolism), and all-cause mortality during the follow-up using propensity score matching., Results: After entering 20 covariates in the current matching analysis, 342 patients who underwent CA and 342 matched patients who received drug therapy, with a median follow-up of 1865 days, were included. The patients who underwent CA were significantly associated with lower incidence of MACE (hazard ratio (HR) 0.56, 95% confidential interval (CI) 0.36-0.86; P = 0.0077), and all-cause mortality (HR 0.47, 95% CI 0.29-0.75; P = 0.0016)., Conclusion: CA was associated with lower incidences of MACE and all-cause mortality for patients with AF as compared with those who received drug therapy. The most common event of MACE in patients who underwent CA was heart failure hospitalization., Clinical Trial Registration: URL: http://www.umin.ac.jp/ctr/index.htm UNIQUE IDENTIFIER: UMIN000005834.

Histone acetylation by epigenetic regulators has been shown to activate the transcription of hypertrophic response genes, which subsequently leads to the development and progression of heart failure. However, nothing is known about the acetylation of the histone tail and globular domains in left ventricular hypertrophy or in heart failure. The acetylation of H3K9 on the promoter of the hypertrophic response gene was significantly increased in the left ventricular hypertrophy stage, whereas the acetylation of H3K122 did not increase in the left ventricular hypertrophy stage but did significantly increase in the heart failure stage. Interestingly, the interaction between the chromatin remodeling factor BRG1 and p300 was significantly increased in the heart failure stage, but not in the left ventricular hypertrophy stage. This study demonstrates that stage-specific acetylation of the histone tail and globular domains occurs during the development and progression of heart failure, providing novel insights into the epigenetic regulatory mechanism governing transcriptional activity in these processes.

Data regarding the associations of anemia (hemoglobin level <13.0 g/dl in men and <12.0 g/dl in women) with clinical outcomes in patients with atrial fibrillation (AF) remains scarce. This study sought to investigate the associations of anemia with the incidences of stroke or systemic embolism, major bleeding, heart failure (HF) hospitalization, and all-cause mortality including its causes, using the data from a Japanese community-based survey, the Fushimi AF Registry. A total of 4,169 AF patients were divided into the 3 groups, based on the baseline hemoglobin level: no (n = 2,622), mild (11.0 to <13.0 g/dl for men and <12.0 g/dl for women; n = 880), and moderate/severe anemia (<11.0 g/dl; n = 667). During a median follow-up of 1,464 days, the incidences of major bleeding, HF hospitalization, and mortality increased with higher rates of cardiac death, in accordance with anemic severity. On multivariate analyses, the higher risk of moderate/severe anemia, relative to no anemia, for major bleeding remained statistically significant (hazard ratio [HR]: 2.00, 95% confidential interval [CI]: 1.48 to 2.72). The risks of those with anemia, relative to no anemia, for HF hospitalization (mild; HR: 1.87, 95% CI: 1.51 to 2.31, and moderate/severe; HR: 2.02, 95% CI: 1.59 to 2.57) as well as for mortality (mild; HR: 1.80, 95% CI: 1.50 to 2.16, and moderate/severe; HR: 2.95, 95% CI: 2.45 to 3.55) were also higher, but not for stroke/systemic embolism. These relations were consistent, regardless of the use of oral anticoagulants. In conclusion, anemia was associated with higher risks of HF hospitalization, mortality, and major bleeding in AF patients., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Pathological stresses such as pressure overload and myocardial infarction induce cardiac hypertrophy, which increases the risk of heart failure. Cacao bean polyphenols have recently gained considerable attention for their beneficial effects on cardiovascular diseases. This study investigated the effect of cacao bean polyphenols on the development of cardiac hypertrophy and heart failure. Cardiomyocytes from neonatal rats were pre-treated with cacao bean polyphenols and then stimulated with 30 µM phenylephrine. C57BL/6j male mice were subjected to sham or transverse aortic constriction surgery and then orally administered with vehicle or cacao bean polyphenols. Cardiac hypertrophy and function were examined by echocardiography. In cardiomyocytes, cacao bean polyphenols significantly suppressed phenylephrine-induced cardiomyocyte hypertrophy and hypertrophic gene transcription. Extracellular signal-regulated kinase 1/2 and GATA binding protein 4 phosphorylation induced by phenylephrine was inhibited by cacao bean polyphenols treatment in the cardiomyocytes. Cacao bean polyphenols treatment at 1200 mg/kg significantly ameliorated left ventricular posterior wall thickness, fractional shortening, hypertrophic gene transcription, cardiac hypertrophy, cardiac fibrosis, and extracellular signal-regulated kinase 1/2 phosphorylation induced by pressure overload. In conclusion, these findings suggest that cacao bean polyphenols prevent pressure overload-induced cardiac hypertrophy and systolic dysfunction by inhibiting the extracellular signal-regulated kinase 1/2-GATA binding protein 4 pathway in cardiomyocytes. Thus, cacao bean polyphenols may be useful for heart failure therapy in humans., Competing Interests: T. M., Y. K., and Y. S. received financial support from Meiji Co., Ltd. (number A185-05). N. S., H. H., Y. M., M. F., K. S., S. S., H. W., and K. H. declare no conflict of interest., (Thieme. All rights reserved.)

Curcumin is a naturally occurring p300-histone acetyltransferase (p300-HAT) inhibitor that suppresses cardiomyocyte hypertrophy and the development of heart failure in experimental animal models. To enhance the therapeutic potential of curcumin against heart failure, we produced a series of synthetic curcumin analogues and investigated their inhibitory activity against p300-HAT. The compound with the strongest activity was further evaluated to determine its effects on cardiomyocyte hypertrophy and pressure overload-induced heart failure in mice. We synthesised five synthetic curcumin analogues and found that a compound we have named GO-Y030 most strongly inhibited p300-HAT activity. Furthermore, 1 μM GO-Y030, in a manner equivalent to 10 µM curcumin, suppressed phenylephrine-induced hypertrophic responses in cultured cardiomyocytes. In mice undergoing transverse aortic constriction surgery, administration of GO-Y030 at a mere 1% of an equivalently-effective dose of curcumin significantly attenuated cardiac hypertrophy and systolic dysfunction. In addition, this low dose of GO-Y030 almost completely blocked histone H3K9 acetylation and eliminated left ventricular fibrosis. A low dose of the synthetic curcumin analogue GO-Y030 effectively inhibits p300-HAT activity and markedly suppresses the development of heart failure in mice.

Background: There is a growing burden of valvular heart disease (VHD) and atrial fibrillation (AF) due to population aging, but data regarding the characteristics and outcomes of patients with AF and concomitant VHD are lacking., Methods and results: The Fushimi AF Registry is a community-based prospective survey of AF patients in Fushimi-ku, Kyoto. Among 3,566 patients with available echocardiographic data, 20% had VHD, consisting of 131 valvular AF (VAF: 3.7%) and 583 nonvalvular AF with VHD (NVAF-VHD: 16.3%). Here, VAF was defined as AF with mitral stenosis or a prosthetic heart valve. AF patients with VHD were older, had more comorbidities with a higher CHADS 2 score, and were prescribed oral anticoagulants more frequently than those without VHD. After adjusting for confounders, VHD was not associated with stroke or systemic embolism, all-cause mortality, or cardiac death. NVAF-VHD was significantly associated with an increased risk of hospitalization for heart failure (adjusted hazard ratio [HR], 1.44; 95% confidence interval [CI], 1.16-1.78), whereas VAF was not (HR, 1.28; 95% CI, 0.86-1.92). Among all types of VHD, aortic valve diseases were associated with a higher risk of cardiac events, whereas mitral valve diseases were not., Conclusions: Although VHD did not significantly affect thromboembolism or mortality, it affected cardiac events depending on type, with aortic valve diseases having higher risk, in Japanese patients with AF.

Data regarding the relation of the type of atrial fibrillation (AF) to the incidence of cardiac events remain scarce. This study sought to investigate the association of AF type with the incidences of cardiac death and heart failure (HF) hospitalization between paroxysmal and sustained (persistent/permanent) AF in the overall population and in age subgroups (≤74, 75 to 84, and ≥85 years), using the data from a Japanese community-based prospective survey, the Fushimi AF Registry. The participants started to be enrolled since March 2011, and follow-up data were available for 4,304 patients by the end of November 2017. Patients with sustained AF (n = 2,187, 50.8%) had more co-morbidities with higher mean CHA 2 DS 2 -VASc score than those with paroxysmal AF (n = 2,117, 49.2%) (sustained vs paroxysmal: 3.57 ± 1.69 vs 3.17 ± 1.67, p <0.001). During a median follow-up of 1,307 (interquartile range: 709 to 2,156) days, the composite of cardiac death and HF hospitalization occurred more frequently in those with sustained AF (event rate: 5.1 vs 2.8 per 100 person-years; p <0.001). On multivariate analysis, sustained AF was independently associated with higher incidence of this composite end point (adjusted hazard ratio [HR]: 1.35, 95% confidence interval [CI]: 1.12 to 1.63, p = 0.002). In age subgroups, this association was observed only in the younger AF patients (≤74 years) (adjusted HR: 2.03, 95% CI: 1.44 to 2.86, p <0.001), but not in the older subgroups (p = 0.018 for interaction). In conclusion, sustained AF was associated with higher incidence of the composite of cardiac death and HF hospitalization than paroxysmal AF, with different relations seen depending on age subgroups., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Rationale: SERCA2a, sarco-endoplasmic reticulum Ca 2+ -ATPase, is a critical determinant of cardiac function. Reduced level and activity of SERCA2a are major features of heart failure. Accordingly, intensive efforts have been made to develop efficient modalities for SERCA2a activation. We showed that the activity of SERCA2a is enhanced by post-translational modification with SUMO1 (small ubiquitin-like modifier 1). However, the roles of other post-translational modifications on SERCA2a are still unknown., Objective: In this study, we aim to assess the role of lysine acetylation on SERCA2a function and determine whether inhibition of lysine acetylation can improve cardiac function in the setting of heart failure., Methods and Results: The acetylation of SERCA2a was significantly increased in failing hearts of humans, mice, and pigs, which is associated with the reduced level of SIRT1 (sirtuin 1), a class III histone deacetylase. Downregulation of SIRT1 increased the SERCA2a acetylation, which in turn led to SERCA2a dysfunction and cardiac defects at baseline. In contrast, pharmacological activation of SIRT1 reduced the SERCA2a acetylation, which was accompanied by recovery of SERCA2a function and cardiac defects in failing hearts. Lysine 492 (K492) was of critical importance for the regulation of SERCA2a activity via acetylation. Acetylation at K492 significantly reduced the SERCA2a activity, presumably through interfering with the binding of ATP to SERCA2a. In failing hearts, acetylation at K492 appeared to be mediated by p300 (histone acetyltransferase p300), a histone acetyltransferase., Conclusions: These results indicate that acetylation/deacetylation at K492, which is regulated by SIRT1 and p300, is critical for the regulation of SERCA2a activity in hearts. Pharmacological activation of SIRT1 can restore SERCA2a activity through deacetylation at K492. These findings might provide a novel strategy for the treatment of heart failure.

Hemodynamic stresses, including hypertension and myocardial infarction, activate neurohumoral factors such as the sympathetic nervous system and the renin-angiotensin system, and can lead to the progression of heart failure. Established pharmacological agents such as angiotensin II receptor blockers (ARBs), angiotensin-converting enzyme (ACE) inhibitors, and β-blockers target extra-cellular molecules and receptors on the cell membrane. These agents have shown some efficacy for the treatment of heart failure, but the long-term survival rate of patients with heart failure remains low. Additional effective pharmacological approaches are urgently required. Our previous studies have demonstrated that curcumin, a natural polyphenol derived from the root of Curcuma longa, prevented the development of heart failure in rat models of myocardial infarction and hypertensive heart disease. However, until recently curcumin's poor water solubility and extremely low bioavailability have presented serious challenges to its clinical applicability. In recent years, highly absorbable curcumin preparations have been developed using methods such as nanoparticle formation and micellization, and there are now high expectations for their wide clinical application. Our group has developed a highly absorbable curcumin formulation called Theracurmin using nanoparticulation and surface processing techniques. Our preliminary data indicated that Theracurmin may improve left ventricular diastolic function. Furthermore, we have already completed and are currently carrying out several clinical trials using Theracurmin against heart failure-related diseases. This paper summarizes and discusses the potential clinical applications of curcumin, focusing on our highly absorbable curcumin formulation, Theracurmin.

Background: The clinical characteristics and outcomes of asymptomatic patients with paroxysmal or persistent/permanent atrial fibrillation (AF) are largely unknown., Methods: The Fushimi AF Registry is a community-based prospective survey of patients with AF who visited the participating medical institutions in Fushimi-ku, Japan. We investigated the clinical characteristics and outcomes of asymptomatic vs symptomatic patients in the paroxysmal AF (PAF; n = 1,837) and persistent/permanent (sustained atrial fibrillation [SAF]; n = 1,912) subgroups., Results: In the PAF group, asymptomatic patients were older (asymptomatic vs symptomatic group, 74.1 vs 71.1 years of age; P < .01), more often male (62.1% vs 55.6%; P < .01), and had a higher CHA 2 DS 2 -VASc (congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus, history of stroke, vascular disease, age 65-74 years, and female sex) score (mean, 3.37 ± 1.73 vs 2.99 ± 1.63; P < .01), whereas the prevalence of major co-morbidities and CHA 2 DS 2 -VASc scores were comparable in the SAF group. Multivariable analysis indicated that age (≥ 75 years), history of stroke/systemic embolism, male sex, and chronic kidney disease were independent determinants of asymptomatic status in the PAF group, whereas age was nonsignificant in the SAF group. During the follow-up period, all-cause mortality was significantly higher (hazard ratio, 1.71 [95% CI, 1.31-2.29]; P < .01) in asymptomatic patients compared with symptomatic patients in the PAF group, whereas it was comparable in the SAF group., Conclusions: Asymptomatic clinical status is associated with older age, male sex, more co-morbidities with a higher stroke risk profile, and a higher incidence of all-cause death in patients with PAF; these characteristics and outcomes were not seen in the SAF group., Trial Registry: UMIN Clinical Trials Registry; No.: UMIN000005834; URL: www.umin.ac.jp/ctr/index.htm., (Copyright © 2017 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Heart failure is a leading cause of cardiovascular mortality in industrialized countries. During development and deterioration of heart failure, cardiomyocytes undergo maladaptive hypertrophy, and changes in the cellular phenotype are accompanied by reinduction of the fetal gene program. Gene expression in cardiomyocytes is regulated by various nuclear transcription factors, co-activators, and co-repressors. The zinc finger protein GATA4 is one such transcription factor involved in the regulation of cardiomyocyte hypertrophy. In response to hypertrophic stimuli such as those involving the sympathetic nervous and renin-angiotensin systems, changes in protein interaction and/or post-translational modifications of GATA4 cause hypertrophic gene transcription in cardiomyocytes. In this article, we focus on cardiac nuclear signaling molecules, especially GATA4, that are promising as potential targets for heart failure therapy.

Background: The mechanism of cardiac energy production against sustained pressure overload remains to be elucidated., Methods and Results: We generated cardiac-specific kinase-dead (kd) calcium/calmodulin-dependent protein kinase kinase-β (CaMKKβ) transgenic (α-MHC CaMKKβkd TG) mice using α-myosin heavy chain (α-MHC) promoter. Although CaMKKβ activity was significantly reduced, these mice had normal cardiac function and morphology at baseline. Here, we show that transverse aortic binding (TAC) in α-MHC CaMKKβkd TG mice led to accelerated death and left ventricular (LV) dilatation and dysfunction, which was accompanied by significant clinical signs of heart failure. CaMKKβ downstream signaling molecules, including adenosine monophosphate-activated protein kinase (AMPK), were also suppressed in α-MHC CaMKKβkd TG mice compared with wild-type (WT) mice. The expression levels of peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α, which is a downstream target of both of CaMKKβ and calcium/calmodulin kinases, were also significantly reduced in α-MHC CaMKKβkd TG mice compared with WT mice after TAC. In accordance with these findings, mitochondrial morphogenesis was damaged and creatine phosphate/β-ATP ratios assessed by magnetic resonance spectroscopy were suppressed in α-MHC CaMKKβkd TG mice compared with WT mice after TAC., Conclusions: These data indicate that CaMKKβ exerts protective effects on cardiac adaptive energy pooling against pressure-overload possibly through phosphorylation of AMPK and by upregulation of PGC-1α. Thus, CaMKKβ may be a therapeutic target for the treatment of heart failure.

Heart failure is one of the leading causes of death throughout the world. During the development and deterioration processes of heart failure, cardiomyocytes undergo maladaptive hypertrophy by altering hypertrophy-related gene expression. The zinc finger protein GATA4 is one of the transcription factors involved in the regulation of cardiomyocyte hypertrophy. In response to hypertrophic stimuli such as the synaptic nervous and rennin-angiotensin systems, GATA4 forms a large complex with various functional proteins including an intrinsic histone acetyltransferase, p300, and the disruption of this complex results in the inhibition of hypertrophic responses in cardiomyocytes. While such a transcriptional signal pathway is recognized as a critical event during cardiomyocyte hypertrophy, pharmacological heart failure therapy that targets this pathway has not been established. In order to develop novel heart failure therapy targeting the pathway in cardiomyocytes, we have studied the potential of curcumin, a p300 histone acetyltransferase inhibitor, as an agent for novel heart failure therapy. In this review, we describe a recent study on the cardiac transcriptional signal pathway, especially p300/GATA4 pathway, and a novel heart failure therapy using curcumin.

Curcumin is an inhibitor of p300 histone acetyltransferase activity, which is associated with the deterioration of heart failure. We reported that native curcumin, at a dosage of 50 mg/kg, prevented deterioration of the systolic function in rat models of heart failure. To achieve more efficient oral pharmacological therapy against heart failure by curcumin, we have developed a novel drug delivery system (DDS) which markedly increases plasma curcumin levels. At the dosage of 0.5 mg/kg, DDS curcumin but not native curcumin restored left ventricular fractional shortening in post-myocardial infarction rats. Thus, our DDS strategy will be applicable to the clinical setting in humans.

Hypertensive heart disease and post-myocardial-infarction heart failure (HF) are leading causes of cardiovascular mortality in industrialized countries. To date, pharmacological agents that block cell surface receptors for neurohormonal factors have been used, but despite such conventional therapy, HF is increasing in incidence worldwide. During the development and deterioration process of HF, cardiomyocytes undergo maladaptive hypertrophy, which markedly influences their gene expression. Regulation of histone acetylation by histone acetyltransferase (eg, p300) and histone deacetylase plays an important role in this process. Increasing evidence suggests that the excessive acetylation of cardiomyocyte nuclei is a hallmark of maladaptive cardiomyocyte hypertrophy. Curcumin inhibits p300-mediated nuclear acetylation, suggesting its usefulness in HF treatment. Clinical application of this natural compound, which is inexpensive and safe, should be established in the near future.

Background: Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is a multiple ligand receptor induced by oxidative stress. However, its role in chronic heart failure remains unknown., Methods and Results: The left ventricular (LV) expression of LOX-1 was examined in a salt-sensitive Dahl rat model of hypertension. Compared with controls, LOX-1 mRNA levels increased by 4.7-fold in the LV with hypertrophy, and by 32-fold in the LV with decreased systolic function. LV LOX-1 mRNA levels strongly correlated with the decrease in LV ejection fraction (EF) (r=-0.772), and with increases in the LV mRNA levels of B-type natriuretic peptide (r=0.814), monocyte chemoattractant protein-1 (r=0.943), transforming growth factor-beta(1) (r=0.936), and a macrophage marker, F4/80 (r=0.560). Serum levels of soluble LOX-1 were significantly elevated in patients with LV systolic dysfunction and hypertrophy, and significantly correlated with the decrease in EF (r=-0.495)., Conclusions: Marked increase in the LV expression of LOX-1 in failing hearts may contribute to increased serum levels, and might be involved in chronic inflammation during the development of heart failure.

Hemodynamic overload in the heart can trigger maladaptive hypertrophy of cardiomyocytes. A key signaling event in this process is nuclear acetylation by histone deacetylases and p300, an intrinsic histone acetyltransferase (HAT). It has been previously shown that curcumin, a polyphenol responsible for the yellow color of the spice turmeric, possesses HAT inhibitory activity with specificity for the p300/CREB-binding protein. We found that curcumin inhibited the hypertrophy-induced acetylation and DNA-binding abilities of GATA4, a hypertrophy-responsive transcription factor, in rat cardiomyocytes. Curcumin also disrupted the p300/GATA4 complex and repressed agonist- and p300-induced hypertrophic responses in these cells. Both the acetylated form of GATA4 and the relative levels of the p300/GATA4 complex markedly increased in rat hypertensive hearts in vivo. The effects of curcumin were examined in vivo in 2 different heart failure models: hypertensive heart disease in salt-sensitive Dahl rats and surgically induced myocardial infarction in rats. In both models, curcumin prevented deterioration of systolic function and heart failure-induced increases in both myocardial wall thickness and diameter. From these results, we conclude that inhibition of p300 HAT activity by the nontoxic dietary compound curcumin may provide a novel therapeutic strategy for heart failure in humans.

Some ANG II receptor type 1 (AT(1)) antagonists are reported to inhibit proinflammatory cytokine production in vitro and in vivo. However, the effects of the drugs on autoimmune diseases are unknown. We tested the hypothesis that olmesartan, a novel AT(1) antagonist, ameliorated experimental autoimmune myocarditis (EAM) in rats attributed to the suppression of inflammatory cytokines as well as to the immunomodulatory action of the heart. We administered olmesartan orally at does of 1, 3, and 10 mg.kg(-1).day(-1) to rats with EAM for 3 wk. The results showed that olmesartan decreased blood pressure significantly compared with the untreated group and markedly reduced the severity of myocarditis associated with the decrease of myocardial macrophage, CD4(+), and CD8(+) T-cell expression by comparison of heart wt-to-body wt ratios, pericardial effusion scores, and macroscopic and microscopic scores. Numbers of myocardial interleukin-1beta (IL-1beta)-positive-staining cells (obtained by immunohistochemistry) and quantities of IL-1beta expression (obtained by Western blotting) were significantly lower in rats with EAM given olmesartan treatment compared with rats given vehicle. Cardiac myosin-specific, delayed-type hypersensitivity was significantly lower in olmesartan-treated rats than in control rats. The cytotoxic activities of lymphocytes in rats with EAM treated with olmesartan were reduced compared with untreated control rats. In vitro study showed that both olmesartan and its active metabolite RNH-6270 suppressed IL-1beta production in U-937 cells and cultured myocytes. Olmesartan ameliorates acute EAM in rats. The cardioprotection of olmesartan may be due to suppression of inflammatory cytokines as well as to suppressive effects of cytotoxic myocardial injury in addition to hemodynamic modifications.

Background: We have developed a hepatocyte growth factor (HGF)-incorporating gelatin hydrogel sheet (HGF sheet), which was designed to release HGF more than 2 weeks in vivo. The present study investigated whether the HGF sheet could prevent the progression of heart failure in stroke-prone spontaneously hypertensive rats., Methods: Stroke-prone spontaneously hypertensive rats at the age of 25 weeks received placement of an HGF sheet on the left ventricular free wall (HGF, n = 10) or sham-operation (control, n = 10). All animals were followed up with Doppler echocardiography during the next 4 weeks and then underwent histologic analysis. The influence of the hydrogel sheet alone was assessed by echocardiography and left ventricular pressure measurements. Survival study was performed (each group, n = 11) at the age of 30 weeks., Results: There were two deaths in the control group and no deaths in the HGF group during the 4 weeks. Fractional shortening was significantly higher, and left ventricular diastolic dimension was significantly smaller in the HGF than in the control group. The slope of the peak early diastolic filling velocity and the ratio of that slope to the slope of the peak filling velocity at atrial contraction were significantly lower in the HGF than the control group. Myocardial fibrosis was lower and capillary density was significantly higher in the HGF than the control group. Placement of the hydrogel sheet alone did not affect any cardiac function compared with sham operation. The survival rate at 10 weeks after the surgery was much higher in the HGF than the control group., Conclusions: The HGF sheet improves cardiac function, reverses left ventricular remodeling, and markedly improves survival in spontaneously hypertensive rats. These beneficial effects are associated with angiogenesis and reduced fibrosis in the left ventricular myocardium.

While left ventricular (LV) reduction surgery (LVR) is a novel treatment for severe heart failure, alteration of signal transduction pathways by this surgery is unknown. LV endothelin-1 plays a critical role in LV remodeling following myocardial infarction (MI). Another possible mechanism of remodeling is myocardial cell loss due to apoptosis. The purpose of the present study was to determine whether the LV endothelin-1 level and apoptosis signaling change after LVR. Adult rats were divided into two groups: non-MI group and MI group, and the MI group was subjected to permanent ligation of the left anterior descending artery. Four weeks later, rats in the MI group were subjected to LVR (LVR group) or a sham operation (OMI group). Two weeks after the second operation, echocardiography revealed that LVR improved LV systolic function and remodeling. Upregulation of LV endothein-1 was detected only in the OMI group but not in the non-MI group nor in the LVR group. The percentage of terminal deoxynucleotidyl transfer-mediated end-labeling of fragmented nuclei (TUNEL)-positive cardiac myocytes was significantly higher in the OMI group than in the LVR group or the non-MI group. Western blotting of extracts from the left ventricle showed that bcl-2 and bcl-xL levels were restored and caspase-3 activation was repressed after LVR. Thus, LVR modulates the expression of endothelin-1 and apoptosis signaling in failing hearts. These alterations of signal transduction pathways might contribute to the beneficial effects of LVR on systolic function in heart failure.

Background: It remains unclear whether circadian variation (CV) of cardiac autonomic nervous activity (CANA) is preserved in patients with chronic heart failure (CHF) as in healthy subjects. We have demonstrated that CANA in CHF patients is largely affected by patient recumbent position., Methods: We studied eight mild to moderate CHF patients and eight age, sex-matched healthy subjects. Each subject underwent 24-h ambulatory ECG monitoring. One channel was used to record the CM5 lead, and another to record the signal of patient position from a newly developed, small-sized detector. By using spectral analysis of heart rate variability, frequency-domain measures were calculated. Normalized high-frequency (HF: 0.15-0.40 Hz) power was used as an index of vagal activity and the low frequency (LF: 0.04-0.15 Hz)/HF power ratio was used as an index of sympathovagal balance. These indexes in the same recumbent position were compared between night (2:00-4:00 a.m.) and morning (6:00-8:00 a.m.)., Results: In healthy subjects, a definite CV of CANA was observed in each recumbent position. In patients with CHF, in each position, normalized HF power was lower in the morning than at night, whereas LF/HF was higher in the morning than at night. Thus, CANA in CHF patients is influenced not only by patient position but also by the time of day., Conclusion: CV of CANA in mild to moderate CHF patients is well preserved when taking patient position into consideration.

Protein arginine methyltransferase 5 (PRMT5) is a well-known epigenetic regulatory enzyme. However, the role of PRMT5-mediated arginine methylation in gene transcription related to cardiac fibrosis is unknown. Here we show that fibroblast-specific deletion of PRMT5 significantly reduces pressure overload-induced cardiac fibrosis and improves cardiac dysfunction in male mice. Both the PRMT5-selective inhibitor EPZ015666 and knockdown of PRMT5 suppress α-smooth muscle actin (α-SMA) expression induced by transforming growth factor-β (TGF-β) in cultured cardiac fibroblasts. TGF-β stimulation promotes the recruitment of the PRMT5/Smad3 complex to the promoter site of α-SMA. It also increases PRMT5-mediated H3R2 symmetric dimethylation, and this increase is inhibited by Smad3 knockdown. TGF-β stimulation increases H3K4 tri-methylation mediated by the WDR5/MLL1 methyltransferase complex, which recognizes H3R2 dimethylation. Finally, treatment with EPZ015666 significantly improves pressure overload-induced cardiac fibrosis and dysfunction. These findings suggest that PRMT5 regulates TGF-β/Smad3-dependent fibrotic gene transcription, possibly through histone methylation crosstalk, and plays a critical role in cardiac fibrosis and dysfunction. Epigenetic mechanisms play a key role in cardiac fibrosis associated with heart failure. Here, the authors show that protein arginine methyltransferase 5 (PRMT5), an epigenetic writer, regulates fibrotic gene transcription through histone methylation in mice. [ABSTRACT FROM AUTHOR]

Aims: We developed an international registry to examine cardiovascular complications of COVID-19. Methods: A REDCap form was created in March 2020 at Mayo Clinic in collaboration with the International Society of Cardiomyopathy, Myocarditis and Heart Failure (ISCMF) and data were entered from April 2020 through April 2021. Results: Of the 696 patients in the COVID-19 Registry, 411 (59.2%) were male and 283 (40.8%) were female, with a sex ratio of 1.5:1 male to female. In total, 95.5% of the patients were from Japan. The average age was 52 years with 31.5% being >65 years of age. COVID-19 patients with a history of cardiovascular disease (CVD) had more pre-existing conditions including type II diabetes (p < 0.0001), cancer (p = 0.0003), obesity (p = 0.001), and kidney disease (p = 0.001). They also had a greater mortality of 10.1% compared to 1.7% in those without a history of CVD (p < 0.0001). The most common cardiovascular conditions in patients with a history of CVD were hypertension (33.7%), stroke (5.7%) and arrhythmias (5.1%). We found that troponin T, troponin I, brain natriuretic peptide (BNP), N-terminal pro-BNP (NT-proBNP), C-reactive protein (CRP), IL-6 and lambda immunoglobulin free light chains (Ig FLC) were elevated above reference levels in patients with COVID-19. Myocarditis is known to occur mainly in adults under the age of 50, and when we examined biomarkers in patients that were ≤50 years of age and had no history of CVD we found that a majority of patients had elevated levels of troponin T (71.4%), IL-6 (59.5%), creatine kinase/CK-MB (57.1%), D-dimer (57.8%), kappa Ig FLC (75.0%), and lambda Ig FLC (71.4%) suggesting myocardial injury and possible myocarditis. Conclusions: We report the first findings to our knowledge of cardiovascular complications from COVID-19 in the first year of the pandemic in a predominantly Japanese population. Mortality was increased by a history of CVD and pre-existing conditions including type II diabetes, cancer, obesity, and kidney disease. Our findings indicate that even in cases where no abnormalities are found in ECG or ultrasound cardiography that myocardial damage may occur, and cardiovascular and inflammatory biomarkers may be useful for the diagnosis. [ABSTRACT FROM AUTHOR]

Objectives: Natriuretic peptides are an important prognostic marker in patients with heart failure (HF). However, little is known regarding their prognostic significance in patients with atrial fibrillation (AF) without HF and natriuretic peptides levels are underused in these patients in daily practice.Methods: The Fushimi AF Registry is a community-based prospective survey of patients with AF in Fushimi-ku, Kyoto, Japan. We investigated patients with AF without HF (defined as prior HF hospitalisation, New York Heart Association functional class≥2 or left ventricular ejection fraction<40%) using the data of B-type natriuretic peptide (BNP, n=388) or N-terminal pro-B-type natriuretic peptide (NT-proBNP, n=771) at enrolment. BNPs were converted to NT-proBNP using a conversion formula. We divided the patients according to quartiles of NT-proBNP levels and compared the backgrounds and outcomes.Results: Of 1159 patients (mean age: 72.1±10.2 years, median CHA2DS2-VASc score: 3 and oral anticoagulant (OAC) prescription: 671 (56%)), the median NT-proBNP level was 488 (IQR 169-1015) ng/L. Patients with high NT-proBNP levels were older, had higher CHA2DS2-VASc scores and had more OAC prescription (all p<0.001). Kaplan-Meier curves demonstrated that NT-proBNP levels were significantly associated with higher incidences of stroke/systemic embolism, all-cause death and HF hospitalisation during a median follow-up period of 5.0 years (log rank, all p<0.001). Multivariable Cox regression analyses revealed that NT-proBNP levels were an independent predictor of adverse outcomes even after adjustment by various confounders.Conclusion: NT-proBNP levels are a significant prognostic marker for adverse outcomes in patients with AF without HF and may have clinical value.Trial Registration Number: UMIN000005834. [ABSTRACT FROM AUTHOR]

Abstract: Human embryonic stem (ES) cell lines are one of the possible sources of cardiac myocytes to be transplanted in patients with end-staged heart failure. However, prior to the application of human of ES cells for heart failure therapy, it is critical to validate their clinical use in large animals such as primates. Cynomolgus monkey ES cells have similar properties to human ES cells and can be used for primate studies. We demonstrate that 24-h stimulation by a histone deacetylase inhibitor, trichostatin A (TSA) facilitated myocardial differentiation of monkey ES cells with embryonic bodies that were seeded on gelatin-coated dishes. TSA-induced acetylating of histone-3/4 and expression of p300, one of the intrinsic histone acetyltransferases. Thus, such induction as well as inhibition of histone deacetylase may be involved in TSA-induced differentiation of cynomolgus monkey ES cells into cardiomyocytes. [Copyright &y& Elsevier]

One of the major manifestations of obesity is an increased production of the adipocyte-derived 16-kDa peptide leptin, which acts mainly on hypothalamic leptin receptors. Leptin receptors are widely distributed in various tissues, including the heart. Whereas increased plasma leptin levels have been reported in patients with congestive heart failure, systemic alterations induced by obesity can affect cardiac hypertrophy, and the direct effects of leptin on cardiac structure and function still remain to be determined. We first exposed primary cardiac myocytes from neonatal rats to leptin for 48 h. This resulted in a significant increase in myocyte long-axis length (P < 0.05 at 50 ng/ml) but not in the short-axis width. Leptin induced the rapid phosphorylation of STAT3 and its DNA binding in cardiac myocytes. Administration of a JAK2 inhibitor, AG-490, completely inhibited all of these effects by leptin. Furthermore, we examined the effect of continuous infusion of leptin for 4 wk following myocardial infarction in mice. Echocardiography demonstrated that left ventricular fractional shortening in the leptin-infused group (28.4 ± 2.8%) was significantly higher than that in the PBS-infused group (18.4 ± 2.2%) following myocardial infarction, Interestingly, left ventricular diastolic dimension in the leptin-infused group (4.56 ± 0.12 mm) was also higher than that in the PBS-infused group (4.13 ± 0.09 mm). These results demonstrate that leptin induces the elongation of cardiac myocytes via a JAK/STAT pathway and chronic leptin infusion causes eccentric dilatation with augmented systolic function after myocardial infarction. [ABSTRACT FROM AUTHOR]

A variety of stresses on the heart initiate a number of subcellular signaling pathways, which finally reach the nuclei of cardiac myocytes and cause myocyte hypertrophy with heart failure. However, common nuclear pathways that lead to this state are unknown. A zinc finger protein, GATA-4, is one of the transcription factors that mediate changes in gene expression during myocardial-cell hypertrophy, p300 not only acts as a transcriptional coactivator of GATA-4, but also possesses an intrinsic histone acetyltransferase activity. In primary cardiac myocytes derived from neonatal rats, we show that stimulation with phenylephrine increased an acetylated form of GATA-4 and its DNA-binding activity, as well as expression of p300. A dominant-negative mutant of p300 suppressed phenylephrine-induced nuclear acetylation, activation of GATA-4-dependent endothelin-1 promoters, and hypertrophic responses, such as increase in cell size and sarcomere organization. In sharp contrast to the activation of cardiac MEK-1, which phosphorylates GATA-4 and causes compensated hypertrophy in vivo, p300-mediated acetylation of mouse cardiac nuclear proteins, including GATA-4, results in marked eccentric dilatation and systolic dysfunction. These findings suggest that p300-mediated nuclear acetylation plays a critical role in the development of myocyte hypertrophy and represents a pathway that leads to decompensated heart failure. [ABSTRACT FROM AUTHOR]

Drug repositioning has recently emerged as a strategy for developing new treatments at low cost. In this study, we used a library of approved drugs to screen for compounds that suppress cardiomyocyte hypertrophy. We identified the antiplatelet drug sarpogrelate, a selective serotonin-2A (5-HT2A) receptor antagonist, and investigated the drug's anti-hypertrophic effect in cultured cardiomyocytes and its effect on heart failure in vivo. Primary cultured cardiomyocytes pretreated with sarpogrelate were stimulated with angiotensin II, endothelin-1, or phenylephrine. Immunofluorescence staining showed that sarpogrelate suppressed the cardiomyocyte hypertrophy induced by each of the stimuli. Western blotting analysis revealed that 5-HT2A receptor level was not changed by phenylephrine, and that sarpogrelate suppressed phenylephrine-induced phosphorylation of ERK1/2 and GATA4. C57BL/6J male mice were subjected to transverse aortic constriction (TAC) surgery followed by daily oral administration of sarpogrelate for 8 weeks. Echocardiography showed that 5 mg/kg of sarpogrelate suppressed TAC-induced cardiac hypertrophy and systolic dysfunction. Western blotting revealed that sarpogrelate suppressed TAC-induced phosphorylation of ERK1/2 and GATA4. These results indicate that sarpogrelate suppresses the development of heart failure and that it does so at least in part by inhibiting the ERK1/2–GATA4 signaling pathway. [ABSTRACT FROM AUTHOR]

Background: Cardiac hypertrophy and fibrosis are hallmarks of cardiac remodeling and are involved functionally in the development of heart failure (HF). However, it is unknown whether Zerumbone (Zer) prevents left ventricular (LV) systolic dysfunction by inhibiting cardiac hypertrophy and fibrosis.Purpose: This study investigated the effect of Zer on cardiac hypertrophy and fibrosis in vitro and in vivo.Study Design/methods: In primary cultured cardiac cells from neonatal rats, the effect of Zer on phenylephrine (PE)-induced hypertrophic responses and transforming growth factor beta (TGF-β)-induced fibrotic responses was observed. To determine whether Zer prevents the development of pressure overload-induced HF in vivo, a transverse aortic constriction (TAC) mouse model was utilized. Cardiac function was evaluated by echocardiography. The changes of cardiomyocyte surface area were observed using immunofluorescence staining and histological analysis (HE and WGA staining). Collagen synthesis and fibrosis formation were measured by scintillation counter and picrosirius staining, respectively. The total mRNA levels of genes associated with hypertrophy (ANF and BNP) and fibrosis (Postn and α-SMA) were measured by qRT-PCR. The protein expressions (Akt and α-SMA) were assessed by western blotting.Results: Zer significantly suppressed PE-induced increase in cell size, mRNA levels of ANF and BNP, and Akt phosphorylation in cardiomyocytes. The TGF-β-induced increase in proline incorporation, mRNA levels of Postn and α-SMA, and protein expression of α-SMA were decreased by Zer in cultured cardiac fibroblasts. In the TAC male C57BL/6 mice, echocardiography results demonstrated that Zer improved cardiac function by increasing LV fractional shortening and reducing LV wall thickness compared with the vehicle group. ZER significantly reduced the level of phosphorylated Akt both in cultured cardiomyocytes treated with PE and in the hearts of TAC. Finally, Zer inhibited the pressure overload-induced cardiac hypertrophy and cardiac fibrosis.Conclusion: Zer ameliorates pressure overload-induced LV dysfunction, at least in part by suppressing both cardiac hypertrophy and fibrosis. [ABSTRACT FROM AUTHOR]

Abstract: Screening for cell surface proteins up-regulated under stress conditions may lead to the identification of new therapeutic targets. To search for genes whose expression was enhanced by treatment with oligomycin, a mitochondrial-F0F1 ATP synthase inhibitor, signal sequence trapping was performed in H9C2 rat cardiac myoblasts. One of the genes identified was that for neural cell adhesion molecule (NCAM, CD56), a major regulator of development, cell survival, migration, and neurite outgrowth in the nervous system. Immunohistochemical analyses in a mouse myocardial infarction model revealed that NCAM was strongly expressed in residual cardiac myocytes in the infarcted region. Increased expression of NCAM was also found during the remodeling period in a rat model of hypertension-induced heart failure. Lentivirus-mediated knockdown of NCAM decreased the cell growth and survival following oligomycin treatment in H9C2 cells. In primary rat neonatal cardiac myocytes, NCAM was also found to be up-regulated and played a protective role following oligomycin treatment. Analyses of downstream signaling revealed that knockdown of NCAM significantly decreased the basal AKT phosphorylation level. In contrast, NCAM mimetic peptide P2d activated AKT and significantly reduced oligomycin-induced cardiomyocyte death, which was abolished by treatment with the PI3K inhibitor LY-294002 as well as overexpression of the dominant-negative AKT mutant. These findings demonstrate that NCAM is a cardioprotective factor up-regulated under metabolic stress in cardiomyocytes and augmentation of this signal improved survival. [Copyright &y& Elsevier]

Introduction: We previously found that a natural p300 histone acetyltransferase (HAT) inhibitor, curcumin, suppresses the development of heart failure. However, curcumin has low bioavailability; therefore, it is important to find analogues to it to enhance its therapeutic potential. In the present study, we focused on C5-curcuminoids, which possess stronger anti-cancer activity than curcumin, and investigated whether they inhibit p300-HAT activity, and therefore whether they may be useful as therapeutic agents for heart failure. Methods & Results: First, an in vitro p300 HAT assay revealed that the IC50 value of GO-Y030, one of the C5-curcumin analogues investigated, was 1.1 μM, while that of curcumin was 9.4 μM. Moreover, the assay revealed that both mono-ketone moiety and 4 alkoxy groups (3, 3', 5, 5') were important for the enhancement of p300-HAT inhibition of GO-Y030. Second, cultured cardiomyocytes were treated with GO-Y030 or curcumin and then stimulated with phenylephrine (PE). 1 μM of GO-Y030 suppressed the following effects to the same extent as 10 μM of curcumin: PE-induced histone H3K9 acetylation, increases in the mRNA levels of ANF and BNP, and an increase in the surface area of cardiomyocytes. Third, C57BL/6j male mice were subjected to transverse aortic constriction (TAC) or sham operation. One day after the operation, TAC mice were randomly assigned to five groups: vehicle, 1 or 50 mg/kg curcumin, and 0.1 or 0.5 mg/kg GO-Y030. Oral administrations were repeated for 6 weeks. Echocardiographic analysis showed that 0.5 mg/kg GO-Y030 prevented a TAC-induced increase in posterior wall thickness and systolic dysfunction to the same extent as 50 mg/kg curcumin. Moreover, 0.5 mg/kg GO-Y030 suppressed increases in HW/BW ratio, myocardial cell diameter, perivascular fibrosis, mRNA levels of ANF and BNP, and histone H3K9 acetylation to the same extent as 50 mg/kg curcumin. Conclusions: These results indicate that the curcumin analog GO-Y030 strongly inhibits p300-HAT activity compared to curcumin and its derivatives in vitro , and that a low dose of GO-Y030 prevented both cardiomyocyte hypertrophy and the development of heart failure. These findings suggest that GO-Y030 may be more effective than curcumin for heart failure therapy. [ABSTRACT FROM AUTHOR]

Background: p300, a histone acetyltransferase, is known to be required for pathological left ventricular hypertrophy (LVH) and the development of heart failure (HF) in vivo. Most previous studies of histone modification have been carried out within histone tail domains such as H3K9, but it has recently been reported that the H3K122 is a novel acetylation site on the histone globular domain, and that its acetylation activates gene transcription by destabilizing histone-DNA binding. However, little is known about the functional difference between H3K9 and H3K122 acetylation in LVH and HF. Hypothesis: We hypothesized that p300 induces epigenetic changes through the acetylation of both the globular domain and the tail domain of histone in LVH and HF. Methods and Results: Cultured rat neonatal primary cardiomyocytes were stimulated with phenylephrine (PE). Western blotting indicated that treatment with PE increased the acetylation of H3K122 and H3K9 in cardiomyocyte hypertrophy. Chromatin-immunoprecipitation (ChIP) assays demonstrated that PE increased the recruitment of acetylated H3K122 and H3K9 onto ANF and BNP promoters. These acetylations were significantly inhibited by p300 knockdown and by treatment with curcumin, a p300-specific HAT inhibitor. The role of p300 HAT activity in histone acetylation was investigated in vivo using mice in which p300 is overexpressed in the heart, thus inducing LVH. In vivo ChIP assays indicated that p300 overexpression increased the recruitment of acetylated H3K122 and H3K9 onto ANF and BNP promoters. In Dahl salt-sensitive rats, in vivo ChIP assays revealed that the acetylation of H3K9 around ANF and BNP promoters was significantly increased at the LVH stage, which preserved systolic function. The acetylation of H3K122 was significantly increased at the HF stage of systolic dysfunction. However, the degree of recruitment of p300 did not differ in the LVH and HF stages. Interestingly, the recruitment of BRG1, a main component of the SWI/SNF complex, was significantly up-regulated at the HF stage compared to the LVH stage. Conclusion: These results suggest that p300 and BRG1 interact to modulate hypertrophic responses through the acetylation of the histone H3 globular domain at the HF stage. This phenomenon may be a key event in the transition from LVH to HF. [ABSTRACT FROM AUTHOR]

Introduction: Pathological stress such as pressure overload and myocardial infarction induces cardiac hypertrophy, which increases the risk of heart failure (HF). Since cocoa products are among the richest sources of polyphenols in our diets, interest in the beneficial properties of cocoa bean polyphenols (CBPs) has increased steadily. However, whether CBPs could contribute to the reduction of cardiovascular risk was still unknown. Hypothesis: The purpose of this study is to investigate the effect of CBPs on the development of cardiac hypertrophy and HF. Methods: Primary cultured cardiomyocytes from neonatal rats were treated with CBPs and then stimulated with phenylephrine (PE). The cardiomyocyte surface area, hypertrophic gene transcriptions of atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP), and phosphorylation of ERK1/2 and GATA4 were measured. C57BL/6j male mice were subjected to sham or transverse aortic constriction (TAC) operation. The mice were orally administrated with vehicle or CBPs for 8 weeks, and cardiac hypertrophy and function were examined. Results: CBPs significantly suppressed PE-induced cardiomyocyte hypertrophy, hypertrophic gene transcriptions, and ERK/GATA4 phosphorylation. Echocardiography showed that TAC-induced cardiac hypertrophy and dysfunction was preserved by treatment with CBPs at 1200 mg/kg. Histological analysis showed that myocardial cell diameter and perivascular fibrosis were significantly reduced in CBPs group compared with control group. CBP treatment inhibited pressure overload-induced ERK1/2 phosphorylation in hearts. Conclusions: CBPs significantly prevented pressure-overload-induced cardiac hypertrophy and systolic dysfunction through ERK1/2/GATA4 pathway, at least in part, in cardiomyocytes. [ABSTRACT FROM AUTHOR]