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Aim: To investigate the association between dental health and incident cardiovascular disease (CVD) in secondary prevention setting., Materials and Methods: A total of 888 patients with known CVD hospitalized in the cardiology unit were prospectively enrolled. We assessed the association between missing teeth and three variables of periodontitis and major adverse cardiovascular events (MACE), defined as a composite of cardiac death, acute myocardial infarction, stroke and hospital re-admission for congestive heart failure., Results: During a median (Q1, Q3) follow-up of 4.6 (1.4, 6.7) years, an additional missing tooth was associated with a 3% (95% confidence interval [CI]: 1%-5%) higher hazard of MACE (p = .004). Compared with patients with 0 to ≤4 missing teeth, periods free from MACE (95% CI) by 5 years of follow-up were, on average, shorter by 0.17 (-0.04 to 0.37) years, 0.26 (0.04-0.49) years and 0.59 (0.34-0.85) years in patients with 5 to ≤7, 8 to ≤13 and >13 missing teeth, respectively. No significant associations were observed between periodontal measures and MACE incidence., Conclusions: In hospitalized patients with existing CVD, the total number of missing teeth was associated with incident MACE., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Aims: A mineralocorticoid receptor antagonist (MRA) is effective in patients with chronic heart failure; however, the effects of the early initiation of an MRA in patients with acute heart failure (AHF) have not been elucidated., Methods and Results: In this multicentre, randomized, double-blind, placebo-controlled, parallel-group study, we focused on the safety and effectiveness of the treatment with eplerenone, a selective MRA in 300 patients with AHF, that is, 149 in the eplerenone group and 151 in the placebo group in 27 Japanese institutions. The key inclusion criteria were (i) patients aged 20 years or older and (ii) those with left ventricular ejection fraction of ≤40%. The primary outcome was a composite of cardiac death or first re-hospitalization due to cardiovascular disease within 6 months. The mean age of the participants was 66.8 years, 27.3% were women, and the median levels of brain natriuretic peptide were 376.0 pg/mL. The incidences of the primary outcome were 19.5% in the eplerenone group and 17.2% in the placebo group [hazard ratio (HR): 1.09, 95% confidence interval (CI): 0.642-1.855]. In prespecified secondary outcomes, HR for the composite endpoint, cardiovascular death, or first re-hospitalization due to heart failure within 6 months was 0.55 (95% CI: 0.213-1.434). The safety profile for eplerenone was as expected., Conclusion: The early initiation of eplerenone in patients with AHF could safely be utilized. The reduction of the incidence of a composite of cardiovascular death or first re-hospitalization for cardiovascular diseases by eplerenone is inconclusive because of inadequate power., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Autophagy is an evolutionarily conserved process for degradation of long-lived proteins and organelles that govern a number of cardiac pathologies which cause heart failure. Indeed, recent investigations have uncovered pathways that regulate autophagy in the heart and underlying mechanisms by which alterations in this process affect cardiac function and structure. One of the major roles of autophagy in cardiomyocytes is the intracellular protein quality control (PQC). Impairment of autophagy causes aggregation of damaged and/or misfolded proteins in cardiomyocytes, thereby damaging the cells which, in turn leads to pathological cardiac remodeling. We have shown previously that the molecular mechanism of autophagy suppression in response to cardiac stress. Activation of mammalian Ste20-like kinase 1 (Mst1) by stress causes autophagy suppression below physiological levels and inhibits PQC, which in turn contributes to cardiac dysfunction. Specifically, Mst1 inhibits autophagy through phosphorylation of Beclin1, enhancement of Beclin1-Bcl-2 interaction and suppression of Vps34. Here, I show recent advances in understanding the role of autophagy in pathological cardiac remodeling and discuss the therapeutic potential of modulating autophagy in heart disease.

A peptide vaccine targeting angiotensin II (Ang II) was recently developed as a novel treatment for hypertension to resolve the problem of noncompliance with pharmacotherapy. Ang II plays a crucial role in the pathogenesis of cardiac remodeling after myocardial infarction (MI), which causes heart failure. In the present study, we examined whether the Ang II vaccine is effective in preventing heart failure. The injection of the Ang II vaccine in a rat model of MI attenuated cardiac dysfunction in association with an elevation in the serum anti-Ang II antibody titer. Furthermore, any detrimental effects of the Ang II vaccine were not observed in the rats that underwent sham operations. Treatment with immunized serum from Ang II vaccine-injected rats significantly suppressed post-MI cardiac dysfunction in MI rats and Ang II-induced remodeling-associated signaling in cardiac fibroblasts. Thus, our present study demonstrates that the Ang II vaccine may provide a promising novel therapeutic strategy for preventing heart failure.

Background: Mitochondrial autophagy is an important mediator of mitochondrial quality control in cardiomyocytes. The occurrence of mitochondrial autophagy and its significance during cardiac hypertrophy are not well understood., Methods and Results: Mice were subjected to transverse aortic constriction (TAC) and observed at multiple time points up to 30 days. Cardiac hypertrophy developed after 5 days, the ejection fraction was reduced after 14 days, and heart failure was observed 30 days after TAC. General autophagy was upregulated between 1 and 12 hours after TAC but was downregulated below physiological levels 5 days after TAC. Mitochondrial autophagy, evaluated by electron microscopy, mitochondrial content, and Keima with mitochondrial localization signal, was transiently activated at ≈3 to 7 days post-TAC, coinciding with mitochondrial translocation of Drp1. However, it was downregulated thereafter, followed by mitochondrial dysfunction. Haploinsufficiency of Drp1 abolished mitochondrial autophagy and exacerbated the development of both mitochondrial dysfunction and heart failure after TAC. Injection of Tat-Beclin 1, a potent inducer of autophagy, but not control peptide, on day 7 after TAC, partially rescued mitochondrial autophagy and attenuated mitochondrial dysfunction and heart failure induced by overload. Haploinsufficiency of either drp1 or beclin 1 prevented the rescue by Tat-Beclin 1, suggesting that its effect is mediated in part through autophagy, including mitochondrial autophagy., Conclusions: Mitochondrial autophagy is transiently activated and then downregulated in the mouse heart in response to pressure overload. Downregulation of mitochondrial autophagy plays an important role in mediating the development of mitochondrial dysfunction and heart failure, whereas restoration of mitochondrial autophagy attenuates dysfunction in the heart during pressure overload., (© 2016 American Heart Association, Inc.)

Background: It is known that HMG-CoA reductase inhibitors (statins) may have a therapeutic benefit in patients with heart failure (HF). However, no studies have yet evaluated the possible interaction of statins and angiotensin-II receptor blockers (ARBs) on left ventricular (LV) function in patients with HF. We hypothesized that statins might alter the effect of ARBs on cardiac function in patients with HF., Methods and Results: We prospectively randomized patients with chronic HF who received the ARB, losartan (LOS group), or the statin, simvastatin (SIM), in combination with LOS (SIM+LOS group) at our hospitals and assessed before and after treatment for 6 months. Although no significant improvement of HF symptoms as evaluated by the New York Heart Association (NYHA) classification was observed in the LOS group, HF symptoms in the SIM+LOS group significantly improved. The percent increase of LV ejection fraction after treatment in the SIM+LOS group was significantly larger than in the LOS group. Furthermore, the plasma brain natriuretic peptide level was significantly lower after treatment in the SIM+LOS group than in the LOS group., Conclusions: Combined statin and ARB therapy significantly improves both symptoms and LV function over time in patients with HF. Thus, the combination of an ARB with a statin may be a useful therapeutic strategy for HF.

Background: Although therapeutic angiogenesis is a most promising strategy for the treatment of myocardial infarction (MI), it remains unknown if and how endogenous angiogenesis inhibitors, such as endostatin, regulate angiogenesis in MI. In the present study the role of endostatin in left ventricular (LV) remodeling and heart failure was tested in a rat MI model., Methods and Results: When exposed to hypoxia, rat cardiomyocytes showed increased expression of endostatin. After MI induction in the rat MI model, endostatin expression was upregulated in cardiomyocytes, and serum endostatin levels were significantly elevated. Anti-endostatin antibody treatment resulted in significantly higher mortality of MI rats than controls. The MI rats with endostatin neutralization displayed adverse LV remodeling and severe heart failure compared with control MI rats. Although angiogenesis was increased, tissue remodeling and interstitial fibrosis were further exaggerated in post-MI hearts by endostatin neutralization. Furthermore, the expression and protease activity of matrix metalloproteinases -2 and -9, and of angiotensin-converting enzyme were markedly elevated by endostatin neutralization., Conclusions: Neutralization of endostatin worsens the symptoms and outcomes of MI in a rat model. The results imply that endogenous endostatin/collagen XVIII may suppress aberrant LV remodeling and heart failure after MI. (Circ J 2010; 74: 109 - 119).

Background: Few reports regarding the definition, epidemiology, and pathophysiology of acute decompensated heart failure (ADHF) are available. The clinical characteristics of 194 consecutive ADHF patients with abrupt onset of symptoms were investigated., Methods and Results: Patients with acute coronary syndromes including acute myocardial infarction, acute pneumonia, severe valvular disease, and end-stage renal disease that required dialysis therapy were excluded. Patients were divided into 2 groups: rapid-progression group, onset within 24 hours before admission (n = 78); and gradual-progression group, onset more than 24 hours before admission (n = 52). No significant differences were observed in the age, gender, prescriptions, and hematological data between the 2 groups. The proportion of patients who drank excessive water was higher in the rapid-progression group. Systolic blood pressure, diastolic blood pressure, heart rate, left ventricular ejection fraction, and left ventricular wall thickness were greater in patients in the rapid-progression group. Indexes indicating left ventricular diastolic function were significantly deteriorated in the rapid-progression group., Conclusion: Excessive water intake, acute hypertension, and diastolic dysfunction are associated with the pathophysiology of abrupt-onset ADHF. Hypertensive patients with diastolic dysfunction should be treated cautiously to prevent the occurrence of ADHF.

Aims: Cyclins and other cell-cycle regulators have been used in several studies to regenerate cardiomyocytes in ischaemic heart failure. However, proliferation of cardiomyocytes induced by nuclear-targeted cyclin D1 (D1NLS) stops after one or two rounds of cell cycles due in part to accumulation of p27Kip1, an inhibitor of cyclin-dependent kinase (CDK). Thus, expression of S-phase kinase-associated protein 2 (Skp2), a negative regulator of p27Kip1, significantly enhances the effect of D1NLS and CDK4 on cardiomyocyte proliferation in vitro. Here, we examined whether Skp2 can also improve cardiomyocyte regeneration and post-ischaemic cardiac performance in vivo., Methods and Results: Wistar rats underwent ischaemia/reperfusion injury by ligation of the coronary artery followed by injection of adenovirus vectors for D1NLS and CDK4 with or without Skp2. Enhanced proliferation of cardiomyocytes in the presence of Skp2 was demonstrated by increased expression of Ki67, a marker of proliferating cells (1.95% vs. 4.00%), and mitotic phosphorylated histone H3 (0.24% vs. 0.58%). Compared with rats that received only D1NLS and CDK4, expression of Skp2 improved left ventricular function as measured by the maximum and minimum rates of change in left ventricular pressure, the left ventricle end-diastolic pressure, left ventricle end-diastolic volume index, and the lung/body weight ratio., Conclusion: Expression of Skp2 enhanced the effect of D1NLS and CDK4 on the proliferation of cardiomyocytes and further contributed to improved post-ischaemic cardiac function. Skp2 might be a versatile tool to improve the effect of cyclins on post-ischaemic regeneration of cardiomyocytes in vivo.

5‐Hydroxy‐3‐methylglutaryl‐CoA reductase inhibitors (statins) have beneficial effects in patients with heart failure (HF), regardless of serum cholesterol levels. However, their synergic effects with angiotensin II receptor blocker (ARB) remain to be established. We assessed the existence and potential underlying mechanisms of the effects of combined ARB [losartan (LOS)] and statin [simvastatin (SIM)] on cardiac function in rats and mice with load‐induced HF. Salt‐loaded Dahl salt‐sensitive (DS) rats were treated with vehicle, LOS, SIM, or LOS + SIM for 8 weeks. To mimic load‐induced HF in vitro, cultured neonatal rat cardiomyocytes (NRCM) were cyclically stretched. We also investigated the effect of LOS + SIM on pressure overload‐induced HF using mice with transverse aortic constriction (TAC). LOS + SIM improved left ventricular (LV) function and reduced LV hypertrophy more than the monotherapies in both salt‐loaded DS rats and TAC‐operated mice. LV‐tissue increases in Rho kinase and matrix metalloproteinase‐9 activity were decreased to a greater extent by LOS + SIM than by LOS and SIM monotherapies. Plasma levels of Exp‐3174, a LOS metabolite, were higher in LOS + SIM‐treated DS rats than in LOS‐treated rats. Stretch‐induced hypertrophy of NRCM pretreated with SIM + Exp‐3174 was significantly attenuated from that with LOS, Exp‐3174, SIM, or LOS + SIM. SIM administration significantly enhanced mitophagy in mouse hearts after TAC. However, LOS + SIM reduced mitophagy, and the salutary effect of SIM in mouse hearts after TAC was abolished in AT1R−/− mice. In conclusion, LOS and SIM have beneficial myocardial effects on load‐induced HF via differential pleiotropic effects. Thus, combination therapy of these drugs thus has potential as a therapeutic strategy for HF. [ABSTRACT FROM AUTHOR]

Abstract: The NADPH oxidases (Nox) are transmembrane proteins dedicated to producing reactive oxygen species (ROS), including superoxide and hydrogen peroxide, by transferring electrons from NAD(P)H to molecular oxygen. Nox2 and Nox4 are expressed in the heart and play an important role in mediating oxidative stress at baseline and under stress. Nox2 is primarily localized on the plasma membrane, whereas Nox4 is found primarily on intracellular membranes, on mitochondria, the endoplasmic reticulum or the nucleus. Although Nox2 plays an important role in mediating angiotensin II-induced cardiac hypertrophy, Nox4 mediates cardiac hypertrophy and heart failure in response to pressure overload. Expression of Nox4 is upregulated by hypertrophic stimuli, and Nox4 in mitochondria plays an essential role in mediating oxidative stress during pressure overload-induced cardiac hypertrophy. Upregulation of Nox4 induces oxidation of mitochondrial proteins, including aconitase, thereby causing mitochondrial dysfunction and myocardial cell death. On the other hand, Noxs also appear to mediate physiological functions, such as erythropoiesis and angiogenesis. In this review, we discuss the role of Noxs in mediating oxidative stress and both pathological and physiological functions of Noxs in the heart. [Copyright &y& Elsevier]

Background: Mitochondrial autophagy is an important mediator of mitochondrial quality control in cardiomyocytes. The occurrence of mitochondrial autophagy and its significance during cardiac hypertrophy are not well understood.Methods and Results: Mice were subjected to transverse aortic constriction (TAC) and observed at multiple time points up to 30 days. Cardiac hypertrophy developed after 5 days, the ejection fraction was reduced after 14 days, and heart failure was observed 30 days after TAC. General autophagy was upregulated between 1 and 12 hours after TAC but was downregulated below physiological levels 5 days after TAC. Mitochondrial autophagy, evaluated by electron microscopy, mitochondrial content, and Keima with mitochondrial localization signal, was transiently activated at ≈3 to 7 days post-TAC, coinciding with mitochondrial translocation of Drp1. However, it was downregulated thereafter, followed by mitochondrial dysfunction. Haploinsufficiency of Drp1 abolished mitochondrial autophagy and exacerbated the development of both mitochondrial dysfunction and heart failure after TAC. Injection of Tat-Beclin 1, a potent inducer of autophagy, but not control peptide, on day 7 after TAC, partially rescued mitochondrial autophagy and attenuated mitochondrial dysfunction and heart failure induced by overload. Haploinsufficiency of either drp1 or beclin 1 prevented the rescue by Tat-Beclin 1, suggesting that its effect is mediated in part through autophagy, including mitochondrial autophagy.Conclusions: Mitochondrial autophagy is transiently activated and then downregulated in the mouse heart in response to pressure overload. Downregulation of mitochondrial autophagy plays an important role in mediating the development of mitochondrial dysfunction and heart failure, whereas restoration of mitochondrial autophagy attenuates dysfunction in the heart during pressure overload. [ABSTRACT FROM AUTHOR]

Abstract: Chemokines play an important role in induction of chemotaxis of immune cells. CCR1 is a chemokine receptor expressed on neutrophils, monocytes, and T lymphocytes. The role of CCR1 in immunity is not well examined. We demonstrated the role of CCR1 on T lymphocytes and the effect of a CCR1 antagonist, BX471 in myocarditis. Lewis rats were immunized with cardiac myosin on day 0 to establish experimental autoimmune myocarditis. Rats were then administered BX471 subcutaneously every day (group BX0: n = 7) or from day 14 (group BX14: n = 7) and were killed on day 21. We confirmed expression of CCR1 in cells infiltrating the myocardium by immunohistochemistry and FACS analysis. The development of myocarditis was almost completely prevented in group BX0, and myocarditis-affected areas were significantly decreased in size in group BX14. Cardiac function was markedly improved. Ribonuclease protection assay showed that the CCR1 antagonist treatment suppressed mRNA expression for IL-6, IL-1β, and TNF-α in the hearts. An antigen-specific T cell proliferation assay was performed with CD4-positive T cells isolated from control rats immunized with cardiac myosin. T cell proliferation was inhibited by the CCR1 antagonist. Additionally, we showed by Western blot that the CCR1 antagonist suppressed ERK1/2 and JNK activities in T cells stimulated with myosin and that IL-2 reversed this suppression. The CCR1 antagonist reduced the severity of EAM by inhibiting cytokine expression and inducing T cell inactivation. Thus, the CCR1 antagonist may provide a novel therapeutic strategy treatment of myocarditis. [Copyright &y& Elsevier]

A response from the authors of the article "Drp1-dependent mitochondrial autophagy plays a protective role against pressure overload-induced mitochondrial dysfunction and heart failure" in the 2016 issue is presented.