Yasuo Sugano

Differential effects of GM-CSF and G-CSF on infiltration of dendritic cells during early left ventricular remodeling after myocardial infarction.

Several lines of evidence suggest that the immune activation after myocardial infarction (MI) induces secondary myocardial injury. Although dendritic cells (DC) are potent regulators of immunity, their role in MI is still undetermined. We investigated the effect of DC modulation by CSF on left ventricular (LV) remodeling after MI. MI was induced by ligation of the left coronary artery in male Wistar rats. G-CSF (20 μg/kg/day, MI-G, n = 33), a GM-CSF inducer (romurtide, 200 μg/kg/day, MI-GM, n = 28), or saline (MI-C, n = 55) was administered for 7 days. On day 14, MI-G animals had higher LV max dP/dt and smaller LV dimensions, whereas MI-GM animals had lower LV max dP/dt and larger LV dimensions than did MI-C animals, despite similar infarct size. In MI-C, OX62+ DC infiltrated the infarcted and border areas, peaking on day 7. Bromodeoxyuridine-positive DC were observed in the border area during convalescence. Infiltration by DC was decreased in MI-G animals and increased in MI-GM animals compared with MI-C (p < 0.05). In the infarcted area, the heat shock protein 70, TLR2 and TLR4, and IFN-γ expression were reduced in MI-G, but increased in MI-GM in comparison with those in MI-C animals. IL-10 expression was higher in MI-G and lower in MI-GM than in MI-C animals. In conclusion, G-CSF improves and GM-CSF exacerbates early postinfarction LV remodeling in association with modulation of DC infiltration. Suppression of DC-mediated immunity could be a new strategy for the treatment of LV remodeling after MI.

Pathophysiological impact of serum fibroblast growth factor 23 in patients with nonischemic cardiac disease and early chronic kidney disease

Although the important role of fibroblast growth factor (FGF)23 on cardiac remodeling has been suggested in advanced chronic kidney disease (CKD), little is known about serum (s)FGF23 levels in patients with heart failure (HF) due to nonischemic cardiac disease (NICD) and early CKD. The present study aimed to investigate sFGF23 levels in NICD patients and identify the responsible factors for the elevation of sFGF23 levels. We prospectively measured sFGF23 levels in consecutive hospitalized NICD patients with early CKD (estimated glomerular filtration rate ≥ 40 ml·min(-1)·1.73 m(-2)) and analyzed the data of both echocardiography and right heart catheterization. Of the 156 NICD patients (estimated glomerular filtration rate range: 41-128 ml·min(-1)·1.73 m(-2)), the most severe HF symptom (New York Heart Association class III-IV, 53% vs. 33%, P = 0.015) was found in the above median sFGF23 (39.1 pg/ml) group compared with the below median sFGF23 group. sFGF23 levels were higher in patients with HF hospitalization history compared with those without HF [median: 46.8 (interquartile range: 38.8-62.7) vs. 34.7 (interquartile range: 29.6-42.4) pg/ml, P < 0.0001]. In the multivariate analysis, HF hospitalization was independently related to elevated sFGF23 levels (P = 0.022). Both systolic dysfunction and high plasma aldosterone concentration were identified as predictors of high sFGF23 levels (P < 0.05). Among the neurohormonal parameters, elevated sFGF23 levels were the only factor to predict a declining left ventricular ejection fraction (P = 0.001). These findings suggest that the progression of HF per se contributes to the elevation of sFGF23 levels even in the early stages of CKD, which leads to further myocardial dysfunction, potentially creating a vicious cycle.

Effect of Corticosteroid Therapy on Long-Term Clinical Outcome and Left Ventricular Function in Patients With Cardiac Sarcoidosis.

BACKGROUND Cardiac involvement is the worst prognostic determinant in patients with sarcoidosis, but the long-term prognostic significance of corticosteroid therapy for cardiac sarcoidosis (CS) remains unclear. METHODS AND RESULTS We examined 83 consecutive patients diagnosed with CS. Patients were divided into 2 groups based on the presence or absence of corticosteroid therapy at diagnosis. Patients with corticosteroid therapy had lower age and higher rate of positive findings in the myocardium on gallium scintigraphy (Ga) at diagnosis than those without. LVEF, biomarkers, and use of cardiovascular medication were similar between the 2 groups. During the follow-up (7.6±4.4 years), corticosteroid therapy was associated with fewer long-term adverse events (overall, P=0.005; cardiac death, P=0.92; symptomatic arrhythmias, P=0.89; heart failure admission, P<0.0001) and a greater % increase in LVEF than those without (7.9±36.3% vs. -16.7±34.8%, P=0.03). On Cox proportional hazards modeling, corticosteroid therapy (HR, 0.41; 95% CI: 0.20-0.89) was an independent determinant of long-term adverse event-free survival, but age, sex, LVEF, and Ga findings were not. CONCLUSIONS Corticosteroid therapy might have a beneficial effect on long-term clinical outcome in CS patients, particularly by reduction of heart failure admission and retarding the progression of LV systolic dysfunction.

Decreased myocardial dendritic cells is associated with impaired reparative fibrosis and development of cardiac rupture after myocardial infarction in humans.

Background Dendritic cells (DC) play pivotal roles in regulating the immune system and inflammatory response. We previously reported DC infiltration in the infarcted heart and its immunoprotective roles in the post‐infarction healing process after experimental myocardial infarction (MI). However, its clinical significance has not been determined. Methods and Results The degree of DC infiltration and its correlation with the post‐infarction healing process in the human infarcted heart were investigated in 24 autopsy subjects after ST‐elevation MI. Patients were divided into two groups according to the presence (n=13) or absence (n=11) of cardiac rupture. The numbers of infiltrated DC and macrophages and the extent of fibrosis in the infarcted area were examined. In the rupture group, CD68+ macrophage infiltration was increased and CD209+ DC, and CD11c+ DC infiltration and the extent of reparative fibrosis were decreased compared with the non‐rupture group, under matched baseline characteristics including the time from onset to death and use of revascularization. Furthermore, there was a significant positive correlation between the number of infiltrating CD209+ DC, and CD11c+ DC and the extent of reparative fibrosis. Conclusions Decreased number of DC in human‐infarcted myocardial tissue was associated with increased macrophage infiltration, impaired reparative fibrosis, and the development of cardiac rupture after MI. These findings suggest a protective role of DC in post‐MI inflammation and the subsequent healing process.

Prognostic value of malnutrition assessed by Controlling Nutritional Status score for long-term mortality in patients with acute heart failure

BACKGROUND The prognostic value of nutritional status is poorly understood and evidence-based nutritional assessment indices are required in acute heart failure (AHF). We investigated the prognostic value of malnutrition assessed by the Controlling Nutritional Status (CONUT) score (range 0-12, higher=worse, consisting of serum albumin, cholesterol and lymphocytes) in AHF patients. METHODS The CONUT score was measured on admission in 635 consecutive AHF patients. The primary outcome was all-cause death. RESULTS Median CONUT score was 3 (interquartile range 2 to 5). During the median follow-up of 324days, CONUT score was independently associated with death (HR 1.26, 95% CI 1.11-1.42, P<0.001) after adjustment for confounders in a multivariate Cox model. The CONUT score demonstrated the best C-statistic for predicting death (0.71) among other common nutritional markers in HF. Furthermore, addition of the CONUT score to an established risk prediction model from the Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure study significantly increased the C-statistic from 0.75 to 0.77 (P=0.02). The net reclassification improvement afforded by CONUT score was 21% for all-cause death, 27% for survival and 49% overall (P<0.001). CONCLUSION Malnutrition assessed by the CONUT score on admission was an independent determinant of long-term death in AHF, and its prognostic value outweighed that of other nutritional indices. Moreover, addition of the score to the existing risk prediction model significantly increased the predictive ability for death, indicating beneficial clinical application of the CONUT score in AHF patients.

Significance of Low Plasma Levels of Brain-Derived Neurotrophic Factor in Patients With Heart Failure

Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family, which regulates neuronal differentiation and functions. Low levels of BDNF are because of psychological stress and potentially play a role in the pathogenesis of depression and cognition disorders. Because psychological stress and depression are associated with increased risk of heart failure (HF), the pathogenic link between HF and psychological status has attracted clinical attention. We hypothesized that plasma BDNF levels might be decreased in patients with HF and that BDNF could be a key factor associated with HF. We evaluated plasma BDNF levels in 242 patients with HF and 80 subjects without HF who are age and gender matched. Plasma BDNF levels were significantly lower in patients with HF (3,712 pg/ml [2,124 to 6,180]) than those without HF (7,247 pg/ml [5,388 to 9,255], p <0.001) and lower in patients with HF with the New York Heart Association functional class III than class I (p = 0.01) and class II (p <0.001). Log BDNF levels correlated negatively with log B-type natriuretic peptide (r = -0.203, p = 0.03) in patients with HF. Of 61 acute decompensated patients with HF, plasma BDNF levels were significantly higher at discharge (4,194 pg/ml [2,356 to 6,916]) compared with those at admission (2,749 pg/ml [1,380 to 4,161], p = 0.003). Multivariate logistic regression analysis identified log BDNF level as a significant correlate with the presence of HF (odds ratio 0.82; 95% confidence interval 0.76 to 0.91, p <0.001). In conclusion, plasma BDNF levels were decreased in patients with HF and associated with HF severity. BDNF could be a potentially clinically useful biomarker of HF reflecting possible cardio-neuronal linkage.

High-mobility group box 1 protein blockade suppresses development of abdominal aortic aneurysm

BACKGROUND Abdominal aortic aneurysm (AAA) expansion is characterized by chronic inflammatory cell infiltration and extracellular matrix degradation. High-mobility group box 1 protein (HMGB1) is one of the damage-associated molecular pattern molecules derived from injured/necrotic and activated inflammatory cells. We investigated the expression of HMGB1 in human AAA and mouse experimental AAA. Then, we evaluated the effect of HMGB1 blockade on AAA formation in the mouse model. METHODS AND RESULTS Human AAA samples showed increased HMGB1 expression compared with normal aortic wall. In a mouse CaCl(2)-induced AAA model, the expression of HMGB1 was increased compared with that in sham, and was positively correlated with matrix metalloproteinase (MMP)-2 and MMP-9 activity. We administered neutralizing anti-HMGB1 antibody (AAA/anti-H) or control antibody (AAA/C) to AAA mice subcutaneously every 3 days for 6 weeks. Treatment with neutralizing anti-HMGB1 antibody suppressed AAA formation, and attenuated elastin fragmentation. HMGB1 blockade markedly reduced the number of macrophages and MMP-2 and MMP-9 activity in aneurysmal tissue. The mRNA level of tumor necrosis factor-α and CD68 in the aorta was reduced in AAA/anti-H compared with AAA/C. CONCLUSIONS Elevation of HMGB1 level in aneurysmal tissue was observed in human AAA and mouse experimental AAA. HMGB1 blockade in a mouse AAA model reduced AAA progression, in association with reduced infiltration of macrophages and MMPs activity. These findings suggest a significant role for HMGB1 in the pathogenesis of AAA.

Erratum to: Prognostic significance of late gadolinium enhancement quantification in cardiac magnetic resonance imaging of hypertrophic cardiomyopathy with systolic dysfunction

Hypertrophic cardiomyopathy (HCM) with systolic dysfunction carries a poor prognosis. Although late gadolinium enhancement (LGE) on cardiac magnetic resonance is associated with adverse cardiac events in HCM and is inversely related to left ventricular ejection fraction (LVEF), it is unknown whether LGE or LVEF more accurately predicts adverse cardiac events in HCM with systolic dysfunction. We retrospectively assessed the extent of LGE with a threshold of 6 standard deviations in 46 consecutive HCM patients with systolic dysfunction defined as LVEF <50 % (average 35 ± 12 %) who underwent cardiac magnetic resonance (35 males, mean age 59 ± 14 years). They were followed up over 1755 ± 594 days. The composite adverse cardiac events end point included cardiovascular death, lethal arrhythmia, cardioembolic stroke, and unplanned heart failure hospitalization. LGE was detected in all patients, and the mean extent was 30 ± 15 %. Twenty-nine patients developed adverse cardiac events. Multivariate Cox proportional hazard analysis revealed the extent of LGE as a good independent predictor of adverse cardiac events. Risk increased with the extent of LGE (hazard ratio = 1.62/10 % increase in LGE, 95 % confidence interval = 1.23–2.15, p < 0.001). LVEF was inversely related to the extent of LGE (r = −0.44; p = 0.002) and was also an independent predictor of adverse cardiac events. Risk decreased with LVEF (hazard ratio = 0.68/10 % increase in LVEF, 95 % confidence interval = 0.51–0.91, p = 0.010). The Akaike information criterion evaluating the fit of a model demonstrated that the extent of LGE was a better independent predictor of MACE than LVEF (Akaike information criterion = 172.20 and 178.09, respectively).The extent of LGE was a good independent predictor of adverse cardiac events and reflected mortality and morbidity more precisely than LVEF in HCM with systolic dysfunction.

Early use of beta-blockers attenuates systemic inflammatory response and lung oxygenation impairment after distal type acute aortic dissection

We have reported that serum C-reactive protein (CRP) elevation is an independent predictor of lung oxygenation impairment (LOI) after distal type acute aortic dissection (AAD). Systemic activation of the inflammatory system after aortic injury may play a role in the development of LOI. The aim of this study is to clarify the effect of beta-blockers on systemic inflammation and the development of LOI after distal type AAD. A total of 49 patients, who were admitted with distal type AAD and treated conservatively, were examined. White blood cell (WBC) count, serum CRP level, and arterial blood gases were measured serially. Forty patients received beta-blocker treatment within 24 h of the onset, while 9 patients received no beta-blocker treatment. Maximum WBC count, maximum CRP level, lowest PaO2/FiO2 (P/F) ratio, and patient background were compared between the two groups. There was no difference between the groups according to age, sex, coronary risk factors, blood pressure, serum level of CRP, WBC count, and oxygenation index on admission. Beta-blocker treatment was associated with lower maximum WBC count (P = 0.0028) and lower maximum serum CRP level (P = 0.0004). The minimum P/F ratio was higher in patients with beta-blocker treatment than in those without (P = 0.0076). Multivariate analysis revealed that administration of a beta-blocker was an independent negative determinant of LOI (P/F ratio ≤200 mmHg). In conclusion, early use of beta-blockers prevented excessive inflammation and LOI after distal type AAD, suggesting a pleiotropic effect of beta-blockers on the inflammatory response after AAD.

Prevalence, determinants, and prognostic significance of delirium in patients with acute heart failure

BACKGROUND Delirium is a serious syndrome in critically ill patients. However, the prognostic impact of delirium and its determinants in acute heart failure (AHF) patients have not been fully elucidated. METHODS We examined 611 AHF patients who were admitted to our institution. Delirium was diagnosed based on the Intensive Care Delirium Screening Checklist (ICDSC). RESULTS Delirium developed in 139 patients (23%) during hospitalization. Patients with delirium had higher incidence of non-cardiovascular death (p=0.046) and worsening heart failure (p<0.001) during hospitalization. Among patients who survived at discharge, the incidence of all-cause death, cardiovascular death and non-cardiovascular death after discharge were significantly higher in patients with delirium than those without (log-rank; p<0.001, p=0.001, p<0.001, respectively) during a median follow-up period of 335days. In multivariable model, the development of delirium was an independent determinant of worsening heart failure during hospitalization (OR: 2.44, 95% CI: 1.27-4.63) and all-cause death after discharge (HR: 2.38, 95% CI: 1.30-4.35). Furthermore, multivariate analysis indicated that history of cerebrovascular disease (OR: 2.13, 95% CI: 1.36-3.35), age (OR: 1.43, 95% CI: 1.15-1.80), log BNP (OR: 1.39, 95% CI: 1.09-1.79), serum albumin (OR: 0.84, 95% CI: 0.76-0.93) and blood glucose levels (OR: 1.03, 95% CI: 1.00-1.06) were independent determinants of delirium. CONCLUSION In patients with AHF, the development of delirium was associated with poor clinical outcomes, suggesting the importance of early screening and careful monitoring of delirium in such patients.