Yuichiro Maekawa

Prognostic significance of peripheral monocytosis after reperfused acute myocardial infarction: A possible role for left ventricular remodeling

OBJECTIVES The aim of this study was to determine the significance of peripheral monocytosis in clinical outcome after reperfused acute myocardial infarction (AMI), especially relating to post-infarct left ventricular (LV) remodeling. BACKGROUND Peripheral monocytosis occurs two to three days after AMI, reflecting infiltration of monocytes and macrophages into the necrotic myocardium. However, the prognostic significance of peripheral monocytosis after AMI remains to be determined. METHODS A total of 149 patients with first Q-wave AMI were studied. White blood cell (WBC) count, percentage of monocytes and serum C-reactive protein level were measured every 24 h for four days after the onset of AMI. We assessed association between peripheral monocytosis and prognosis including pump failure, LV aneurysm and long-term outcome after AMI. RESULTS Patients with pump failure (p < 0.0001) or LV aneurysm (p = 0.005) had higher peak monocyte counts than those without these complications. Predischarge left ventriculography revealed that peak monocyte count was positively correlated with LV end-diastolic volume (p = 0.024) and negatively correlated with ejection fraction (p = 0.023). Multivariate analyses showed that peak monocyte count > or = 900/mm(3) was an independent determinant of pump failure (relative risk [RR] 9.83, p < 0.0001), LV aneurysm (RR 4.78, p = 0.046) and cardiac events (RR 6.30, p < 0.0001), including readmission for heart failure, recurrent myocardial infarction and cardiac deaths, including sudden deaths. CONCLUSIONS Peripheral monocytosis is associated with LV dysfunction and LV aneurysm, suggesting a possible role of monocytes in the development of LV remodeling after reperfused AMI.

Impaired Heart Contractility in Apelin Gene–Deficient Mice Associated With Aging and Pressure Overload

Apelin constitutes a novel endogenous peptide system suggested to be involved in a broad range of physiological functions, including cardiovascular function, heart development, control of fluid homeostasis, and obesity. Apelin is also a catalytic substrate for angiotensin-converting enzyme 2, the key severe acute respiratory syndrome receptor. The in vivo physiological role of Apelin is still elusive. Here we report the generation of Apelin gene–targeted mice. Apelin mutant mice are viable and fertile, appear healthy, and exhibit normal body weight, water and food intake, heart rates, and heart morphology. Intriguingly, aged Apelin knockout mice developed progressive impairment of cardiac contractility associated with systolic dysfunction in the absence of histological abnormalities. We also report that pressure overload induces upregulation of Apelin expression in the heart. Importantly, in pressure overload–induced heart failure, loss of Apelin did not significantly affect the hypertrophy response, but Apelin mutant mice developed progressive heart failure. Global gene expression arrays and hierarchical clustering of differentially expressed genes in hearts of banded Apelin−/y and Apelin+/y mice showed concerted upregulation of genes involved in extracellular matrix remodeling and muscle contraction. These genetic data show that the endogenous peptide Apelin is crucial to maintain cardiac contractility in pressure overload and aging.

Regulatory Role of Dendritic Cells in Postinfarction Healing and Left Ventricular Remodeling

Background— Inflammation and immune responses are integral components in the healing process after myocardial infarction. We previously reported dendritic cell (DC) infiltration in the infarcted heart; however, the precise contribution of DC in postinfarction healing is unclear. Methods and Results— Bone marrow cells from CD11c-diphtheria toxin receptor/green fluorescent protein transgenic mice were transplanted into lethally irradiated wild-type recipient mice. After reconstitution of bone marrow–derived cells, the recipient mice were treated with either diphtheria toxin (DC ablation) or vehicle (control), and myocardial infarction was created by left coronary ligation. CD11c+ green fluorescent protein–positive DCs expressing CD11b and major histocompatibility complex class II were recruited into the heart, peaking on day 7 after myocardial infarction in the control group. Mice with DC ablation for 7 days showed deteriorated left ventricular function and remodeling. The DC-ablated group demonstrated enhanced and sustained expression of inflammatory cytokines such as interleukin-1&bgr;, interleukin-18, and tumor necrosis factor-&agr;, prolonged extracellular matrix degradation associated with a high level of matrix metalloproteinase-9 activity, and diminished expression level of interleukin-10 and endothelial cell proliferation after myocardial infarction compared with the control group. In vivo analyses revealed that DC-ablated infarcts had enhanced monocyte/macrophage recruitment. Among these cells, marked infiltration of proinflammatory Ly6Chigh monocytes and F4/80+ CD206− M1 macrophages and, conversely, impaired recruitment of anti-inflammatory Ly6Clow monocytes and F4/80+ CD206+ M2 macrophages in the infarcted myocardium were identified in the DC-ablated group compared with the control group. Conclusions— These results suggest that the DC is a potent immunoprotective regulator during the postinfarction healing process via its control of monocyte/macrophage homeostasis.

Role of high-mobility group box 1 protein in post-infarction healing process and left ventricular remodelling

AIMS High-mobility group box 1 protein (HMGB1) is one of the recently defined damage-associated molecular pattern molecules derived from necrotic cells and activated macrophages. We investigated clinical implications of serum HMGB1 elevation in patients with acute myocardial infarction (MI). Then, we evaluated the effect of HMGB1 blockade on post-MI left ventricular (LV) remodelling in a rat MI model. METHODS AND RESULTS Serum HMGB1 levels were examined in patients with ST-elevation MI (n = 35). A higher peak serum HMGB1 level was associated with pump failure, cardiac rupture, and in-hospital cardiac death. Then, an experimental MI model was induced in male Wistar rats. The mRNA and protein expression of HMGB1 were increased in the infarcted area compared with those values observed in sham-operated rats. We administered neutralizing anti-HMGB1 antibody (MI/anti-H) or control antibody (MI/C) to MI rats subcutaneously for 7 days. The mRNA levels of tumour necrosis factor-alpha and interleukin-1beta and the number of macrophages in the infarcted area were reduced on day 3 in MI/anti-H rats compared with MI/C rats. Interestingly, HMGB1 blockade resulted in thinning and expansion of the infarct scar and marked hypertrophy of the non-infarcted area on day 14. CONCLUSION Elevated serum HMGB1 levels were associated with adverse clinical outcomes in patients with MI. However, HMGB1 blockade in a rat MI model aggravated LV remodelling, possibly through impairment of the infarct-healing process. HMGB1, a novel predictor of adverse clinical outcomes after MI, may have an essential role in the appropriate healing process after MI.

Curcumin prevents and reverses murine cardiac hypertrophy

Chromatin remodeling, particularly histone acetylation, plays a critical role in the progression of pathological cardiac hypertrophy and heart failure. We hypothesized that curcumin, a natural polyphenolic compound abundant in the spice turmeric and a known suppressor of histone acetylation, would suppress cardiac hypertrophy through the disruption of p300 histone acetyltransferase-dependent (p300-HAT-dependent) transcriptional activation. We tested this hypothesis using primary cultured rat cardiac myocytes and fibroblasts as well as two well-established mouse models of cardiac hypertrophy. Curcumin blocked phenylephrin-induced (PE-induced) cardiac hypertrophy in vitro in a dose-dependent manner. Furthermore, curcumin both prevented and reversed mouse cardiac hypertrophy induced by aortic banding (AB) and PE infusion, as assessed by heart weight/BW and lung weight/BW ratios, echocardiographic parameters, and gene expression of hypertrophic markers. Further investigation demonstrated that curcumin abrogated histone acetylation, GATA4 acetylation, and DNA-binding activity through blocking p300-HAT activity. Curcumin also blocked AB-induced inflammation and fibrosis through disrupting p300-HAT-dependent signaling pathways. Our results indicate that curcumin has the potential to protect against cardiac hypertrophy, inflammation, and fibrosis through suppression of p300-HAT activity and downstream GATA4, NF-kappaB, and TGF-beta-Smad signaling pathways.

Impact of periprocedural bleeding on incidence of contrast-induced acute kidney injury in patients treated with percutaneous coronary intervention.

OBJECTIVES This study sought to evaluate the association between contrast-induced acute kidney injury (CI-AKI) after percutaneous coronary intervention and severity of bleeding estimated from periprocedural hemoglobin (Hb) measurement. BACKGROUND The relationship between CI-AKI and bleeding in contemporary practice remains controversial. METHODS In a retrospective analysis of the prospectively maintained Japan Cardiovascular Database-Keio Interhospital Cardiovascular Studies (JCD-KICS) multicenter registry, we divided 2,646 consecutive patients into 5 groups according to the change of Hb level after compared with before percutaneous coronary intervention: patients without a decrease in Hb level (group A) and patients with a decreased Hb level: <1 g/dl (group B); 1 to <2 g/dl (group C); 2 to <3g/dl (group D); and >3 g/dl (group E). CI-AKI was defined as an increase in serum creatinine level ≥ 0.5 mg/dl or ≥ 25% above baseline values at 48 h after administration of contrast media. Procedure and outcome variables were compared. RESULTS The mean patient age was 67 ± 11 years. Of the 2,646 patients, CI-AKI developed in 315 (11.9%). The CI-AKI incidence was 6.2%, 7.5%, 10.7%, 17.0%, and 26.2%, in groups A through E, respectively (p < 0.01), whereas the incidence of major bleeding was 0.7%, 1.3%, 2.0%, 4.1%, and 28.3%, respectively (p < 0.01). CI-AKI was associated with higher rates of mortality (5.4% vs. 0.6%, p < 0.01) and of composite of heart failure, cardiogenic shock, and death (16.5% vs. 2.8%, p < 0.01). CONCLUSIONS Periprocedural bleeding was significantly associated with CI-AKI, with CI-AKI incidence correlating with bleeding severity.

Connecting the Missing Link Between Dilated Cardiomyopathy and Viral Myocarditis Virus, Cytoskeleton, and Innate Immunity

Myocarditis classically refers to inflammation of the heart muscle. The mechanisms include host immune dysregulation and viral triggers such as coxsackievirus (CVB), adenovirus, parvovirus, and hepatitis C virus. The pathophysiology is initiated by viral proliferation in a susceptible host, inducing host immune response. The latter, when exuberant, leads to myocyte destruction and dilated cardiomyopathy.1,2 Clinically, patients with viral myocarditis will spontaneously recover in one third of cases, persist with the disease in one third, and deteriorate in another third of the cases. Article p 94 Recent biopsy series in patients with dilated cardiomyopathy have revealed an interesting situation in which patients with symptoms of heart failure may show the presence of the viral genome alone, without any evidence of an overt inflammatory process.3 This raises the question of whether the virus can be directly responsible for the cardiomyopathy or whether it is merely an incidental bystander. Viruses are exquisitely designed nanoparticles packaged with just the critical amount of genetic material to allow them to adapt to changing host and environmental conditions and to pass on genetic material to progeny. CVBs are single-stranded RNA viruses that have natural tropism for gut epithelial cells, immune cells, neurons, and cardiomyocytes. All strains of CVBs use the coxsackie–adenoviral receptor protein to gain entry into host cells (Figure).4 The coxsackie–adenoviral receptor molecule is a critical tight-junction protein important for cell–cell communication and for maintenance of cell membrane integrity. Interestingly, viruses such as CVB must use host signaling mechanisms, including tyrosine kinases such as Abl, fyn, or p56 lck , to rearrange host actin and cytoskeleton and thus gain entry into the host cell and release viral RNA into the cytoplasm.5,6 The signaling pathways that lead from coxsackieviral (CVB) infection to the disruption of the dystrophin–sarcoglycans complex and activation of innate …

Serum C-reactive protein elevation in left ventricular remodeling after acute myocardial infarction - Role of neurohormones and cytokines

BACKGROUND We previously reported that increased peak serum C-reactive protein (CRP) level after acute myocardial infarction (AMI) was a major predictor of cardiac rupture and long-term outcome. The aim of this study was to clarify the role of serum CRP elevation as a possible marker of left ventricular (LV) remodeling after AMI. METHODS We prospectively studied 31 patients who underwent primary angioplasty for a first anterior Q-wave AMI. Peak serum CRP level was determined by serial measurements after admission. LV volume and the plasma levels of various neurohormones and cytokines were measured on admission, and 2 weeks and 6 months after AMI. RESULTS Patients with higher peak CRP levels (above the median) had a greater increase in LV end-diastolic volume during 2 weeks after AMI (+21+/-14 vs. +5+/-6 ml/m(2), P=0.001) and a lower ejection fraction (45+/-11 vs. 53+/-7%, P=0.02) than those with lower CRP levels, associated with a higher incidence of pump failure, atrial fibrillation, and LV aneurysm. Plasma levels of norepinephrine, brain natriuretic peptide, and interleukin-6 2 weeks after AMI were higher in the high CRP group than in the low CRP group. CONCLUSIONS Increased peak serum CRP level was associated with a greater increase in LV volume after anterior AMI. Plasma norepinephrine and interleukin-6 levels were increased in patients with higher CRP levels, suggesting a possible role of sympathetic activation and enhanced immune response in the development of LV remodeling after AMI.

Survival and Cardiac Remodeling After Myocardial Infarction Are Critically Dependent on the Host Innate Immune Interleukin-1 Receptor-Associated Kinase-4 Signaling A Regulator of Bone Marrow-Derived Dendritic Cells

Background— The innate immune system greatly contributes to the inflammatory process after myocardial infarction (MI). Interleukin-1 receptor–associated kinase-4 (IRAK-4), downstream of Toll/interleukin-1 receptor signaling, has an essential role in regulating the innate immune response. The present study was designed to determine the mechanism by which IRAK-4 is responsible for the cardiac inflammatory process, which consequently affects left ventricular remodeling after MI. Methods and Results— Experimental MI was created in IRAK-4−/− and wild-type mice by left coronary ligation. Mice with a targeted deletion of IRAK-4 had an improved survival rate at 4 weeks after MI. IRAK-4−/− mice also demonstrated attenuated cardiac dilation and decreased inflammation in the infarcted myocardium, which was associated with less proinflammatory and Th1 cytokine expression mediated by suppression of nuclear factor-&kgr;B and c-Jun N-terminal kinase activation. IRAK-4−/− mice had fewer infiltrations of CD45+ leukocytes and CD11c+ dendritic cells, inhibition of apoptosis, and reduced fibrosis and nitric oxide production. Cardiac dendritic cells in IRAK-4−/− mice were relatively immature or functionally naïve after MI in that they demonstrated less cytokine and costimulatory molecule gene expression. Furthermore, IRAK-4−/− dendritic cells have less mobilization capacity. Transfer of wild type–derived bone marrow dendritic cells into IRAK-4−/− mice for functional dendritic cell reconstitution negated the survival advantage and reduced the cardiac dilation observed with IRAK-4−/− mice at 28 days after MI. Conclusions— Deletion of IRAK-4 has favorable effects on survival and left ventricular remodeling after MI through modification of the host inflammatory process by blunting the detrimental bone marrow dendritic cells mobilization after myocardial ischemia.

Early Use of Beta-Blockers Is Associated with Attenuation of Serum C-Reactive Protein Elevation and Favorable Short-Term Prognosis after Acute Myocardial Infarction

Background: We have reported that a marked elevation in serum C-reactive protein (CRP) level is a predictor for infarct expansion and cardiac rupture after AMI. Although β-blockers prevent cardiac rupture after AMI, their effect on serum CRP elevation has not been determined. Methods: We studied a total of 154 patients with first Q-wave AMI. Patients complicated by pump failure were excluded from this study. Eighty-two patients received β-blocker treatment within 24 h of the onset of AMI, while 72 patients received no β-blocker treatment. Peak serum creatine kinase (CK) and CRP levels were determined by serial measurements. Results: There was no difference between the groups according to age, sex, coronary risk factors, pre-infarction angina, infarct site, prior use of cardiovascular drugs, use of revascularization therapy, and prevalence of multivessel disease. β-Blocker treatment was associated with a lower peak CRP level (6.9 ± 6.1 vs.10.8 ± 9.3 mg/dl, p = 0.002), a shorter duration from the onset to the peak CRP level (2 ± 1 vs. 3 ± 2 days, p < 0.0001), a lower incidence of cardiac rupture (p = 0.03) and lower in-hospital cardiac mortality (p = 0.02), despite similar peak CK levels. Conclusion: The early use of β-blockers is associated with decreased serum CRP level and a favorable clinical outcome after first Q-wave AMI, suggesting some beneficial effects of β-blockers on infarct healing after AMI.