Taro Narumi

The prognostic importance of objective nutritional indexes in patients with chronic heart failure

BACKGROUND Although malnutrition indicates an unfavorable prognosis in some clinical settings, the association between nutritional indexes and outcomes for patients with chronic heart failure (CHF) is unclear. METHODS AND RESULTS All the previously established objective nutritional indexes were evaluated. The controlling nutritional status score (CONUT), prognostic nutritional index (PNI), and geriatric nutritional risk index (GNRI) were determined for 388 consecutive patients with CHF (mean age 69.6±12.3 years). The prevalence of malnutrition in this cohort was 60-69%. Patients were followed prospectively, with the endpoints being death due to a cardiovascular event or re-hospitalization. There were 130 events, including 33 deaths and 97 re-hospitalizations, during a mean follow-up period of 28.4 months. Patients experiencing cardiovascular events showed impaired nutritional status, higher CONUT scores, lower PNI scores, and lower GNRI scores, compared with those who did not experience cardiovascular events. CONUT score [hazard ratio 40.9, 95% confidence interval (CI) 10.8-154.8], PNI score (hazard ratio 6.4, 95% CI 5.4-25.1), and GNRI score (hazard ratio 11.6, 95% CI 3.7-10.0) were independently associated with cardiovascular events. Kaplan-Meier analysis showed that there was a significantly higher incidence of cardiovascular events in patients who were malnourished than in those who were not. CONCLUSION Malnutrition was common in patients with CHF. Evaluation of nutritional status may provide additional prognostic information in patients with CHF.

Cardiac nuclear high mobility group box 1 prevents the development of cardiac hypertrophy and heart failure

Aims High mobility group box 1 (HMGB1) is an abundant and ubiquitous nuclear DNA-binding protein that has multiple functions dependent on its cellular location. HMGB1 binds to DNA, facilitating numerous nuclear functions including maintenance of genome stability, transcription, and repair. However, little is known about the effects of nuclear HMGB1 on cardiac hypertrophy and heart failure. The aim of this study was to examine whether nuclear HMGB1 plays a role in the development of cardiac hypertrophy induced by pressure overload. Methods and results Analysis of human biopsy samples by immunohistochemistry showed decreased nuclear HMGB1 expression in failing hearts compared with normal hearts. Nuclear HMGB1 decreased in response to both endothelin-1 (ET-1) and angiotensin II (Ang II) stimulation in neonatal rat cardiomyocytes, where nuclear HMGB1 was acetylated and translocated to the cytoplasm. Overexpression of nuclear HMGB1 attenuated ET-1 induced cardiomyocyte hypertrophy. Thoracic transverse aortic constriction (TAC) was performed in transgenic mice with cardiac-specific overexpression of HMGB1 (HMGB1-Tg) and wild-type (WT) mice. Cardiac hypertrophy after TAC was attenuated in HMGB1-Tg mice and the survival rate after TAC was higher in HMGB1-Tg mice than in WT mice. Induction of foetal cardiac genes was decreased in HMGB1-Tg mice compared with WT mice. Nuclear HMGB1 expression was preserved in HMGB1-Tg mice compared with WT mice and significantly attenuated DNA damage after TAC was attenuated in HMGB1-TG mice. Conclusion These results suggest that the maintenance of stable nuclear HMGB1 levels prevents hypertrophy and heart failure by inhibiting DNA damage.

Impact of serum omentin-1 levels on cardiac prognosis in patients with heart failure

BackgroundVarious adipokines are reported to be associated with the development of heart failure (HF) through insulin resistance and chronic inflammation. Omentin-1 is a novel adipokine and is associated with incident coronary artery disease. However, it remains unclear whether serum omentin-1 levels are associated with cardiac prognosis in patients with HF.MethodsWe measured serum omentin-1 levels at admission in 136 consecutive patients with HF, and 20 control subjects without signs of significant heart disease. We prospectively followed patients with HF to endpoints of cardiac death or re-hospitalization for worsening HF.ResultsSerum omentin-1 levels were markedly lower in HF patients with cardiac events compared with to without. The patients who were in New York Heart Association (NYHA) functional class IV showed significantly lower serum omentin-1 levels compared to those in class II and III, whereas serum omentin-1 levels did not correlate with serum brain natriuretic peptide levels (r = 0.217, P = 0.011). We divided the HF patients into three groups based on the tertiles of serum omentin-1 level (low T1, middle T2, and high T3). Multivariate Cox hazard analysis showed that the lowest serum omentin-1 level (T1) was independently associated with cardiac events after adjustment for confounding factors (hazard ratio 5.78, 95% confidence interval 1.20-12.79). We divided the HF patients into two groups according to the median serum omentin-1 levels. Kaplan-Meier analysis revealed that the patients with low serum omentin-1 levels had a higher risk of cardiac events compared with those with high serum omentin-1 levels (log-rank test p < 0.001).ConclusionDecreased serum omentin-1 levels were associated with a poor cardiac outcome in patients with HF.

Sarcopenia evaluated by fat-free mass index is an important prognostic factor in patients with chronic heart failure.

BACKGROUND AND AIM Chronic heart failure (CHF) is a major cause of morbidity and mortality, and cardiac cachexia and sarcopenia are serious complications associated with weight loss and increased catabolism. Fat-free mass index (FFMI) is an indicator of resting energy expenditure and is used for the clinical diagnosis of sarcopenia. In the present study, we investigated the impact of sarcopenia, as evaluated by FFMI, on cardiac prognosis in patients with CHF. METHODS AND RESULTS We calculated FFMI in 267 CHF patients who were prospectively followed until they died due to cardiac event, or until they were re-hospitalized. Fat-free mass (FFM) was estimated by the formula [FFM (kg)=7.38+0.02908×urinary creatinine (mg/day)] and normalized by the square of the patients height in meters to calculate FFMI. During the follow-up periods, there were 83 cardiac events, including 19 cardiac deaths. FFMI was lower in patients with cardiac events than in those without (17.0 kg/m(2) vs. 17.6 kg/m(2), P=0.045). Multivariate Cox hazard analysis revealed that decreased FFMI was associated with an unfavorable outcome (adjusted hazard ratio 0.68, 95% confidence interval 0.47-0.98). The patients were divided into two groups according to their median FFMI. The Kaplan-Meier analysis revealed that significantly higher cardiac event rate was observed in the low-FFMI group (log-rank test, P=0.017). CONCLUSIONS Decreased FFMI was associated with an unfavorable prognosis in patients with CHF.

High-mobility group box 1-mediated heat shock protein beta 1 expression attenuates mitochondrial dysfunction and apoptosis

AIMS Apoptosis of cardiomyocytes is thought to account for doxorubicin cardiotoxicity as it contributes to loss of myocardial tissue and contractile dysfunction. Given that high-mobility group box 1 (HMGB1) is a nuclear DNA-binding protein capable of inhibiting apoptosis, we aimed to clarify the role of HMGB1 in heat shock protein beta 1 (HSPB1) expression during doxorubicin-induced cardiomyopathy. METHODS AND RESULTS Mitochondrial damage, cardiomyocyte apoptosis, and cardiac dysfunction after doxorubicin administration were significantly attenuated in mice with cardiac-specific overexpression of HMGB1 (HMGB1-Tg) compared with wild type (WT) -mice. HSPB1 levels after doxorubicin administration were significantly higher in HMGB1-Tg mice than in WT mice. Transfection with HMGB1 increased the expression of HSPB1 at both the protein and mRNA levels, and HMGB1 inhibited mitochondrial dysfunction and apoptosis after exposure of cardiomyocytes to doxorubicin. HSPB1 silencing abrogated the inhibitory effect of HMGB1 on cardiomyocyte apoptosis. Doxorubicin increased the binding of HMGB1 to heat shock factor 2 and enhanced heat shock element promoter activity. Moreover, HMGB1 overexpression greatly enhanced heat shock element promoter activity. Silencing of heat shock factor 2 attenuated HMGB1-dependent HSPB1 expression and abrogated the ability of HMGB1 to suppress cleaved caspase-3 accumulation after doxorubicin stimulation. CONCLUSIONS We report the first in vivo and in vitro evidence that cardiac HMGB1 increases HSPB1 expression and attenuates cardiomyocyte apoptosis associated with doxorubicin-induced cardiomyopathy. Cardiac HMGB1 increases HSPB1 expression in cardiomyocytes in a heat shock factor 2-dependent manner.

Association of heart-type fatty acid-binding protein with cardiovascular risk factors and all-cause mortality in the general population: the Takahata study.

Background Despite many recent advances in medicine, preventing the development of cardiovascular diseases remains a challenge. Heart-type fatty acid-binding protein (H-FABP) is a marker of ongoing myocardial damage and has been reported to be a useful indicator for future cardiovascular events. However, it remains to be determined whether H-FABP can predict all-cause and cardiovascular deaths in the general population. Methods and Results This longitudinal cohort study included 3,503 subjects who participated in a community-based health checkup with a 7-year follow-up. Serum H-FABP was measured in registered subjects. The results demonstrated that higher H-FABP levels were associated with increasing numbers of cardiovascular risk factors, including hypertension, diabetes mellitus, obesity, and metabolic syndrome. There were 158 deaths during the follow-up period, including 50 cardiovascular deaths. Deceased subjects had higher H-FABP levels compared to surviving subjects. Multivariate Cox proportional hazard regression analysis revealed that H-FABP is an independent predictor of all-cause and cardiovascular deaths after adjustments for confounding factors. Subjects were divided into four quartiles according to H-FABP level, and Kaplan-Meier analysis demonstrated that the highest H-FABP quartile was associated with the greatest risks for all-cause and cardiovascular deaths. Net reclassification index and integrated discrimination index were significantly increased by addition of H-FABP to cardiovascular risk factors. Conclusions H-FABP level was increased in association with greater numbers of cardiovascular risk factors and was an independent risk factor for all-cause and cardiovascular deaths. H-FABP could be a useful indicator for the early identification of high-risk subjects in the general population.

Midkine exacerbates pressure overload-induced cardiac remodeling.

Midkine is a multifunctional growth factor, and its serum levels are increased with the functional severity of heart failure. This study aimed to examine the role of midkine in heart failure pathogenesis. Midkine expression levels were increased in the kidney and lung after transverse aortic constriction (TAC) surgery, but not sufficiently increased in the heart. After TAC, phosphorylation of extracellular signal-regulated kinase1/2 and AKT, and the expression levels of foetal genes in the heart were considerably increased in transgenic mice with cardiac-specific overexpression of midkine (MK-Tg) compared with wild-type (WT) mice. MK-Tg mice showed more severe cardiac hypertrophy and dysfunction, and showed lower survival rate after TAC than WT mice. We conclude that midkine plays a critical role in cardiac hypertrophy and remodelling.

A Novel Mouse Model of Aortic Valve Stenosis Induced by Direct Wire Injury

Objective—The response-to-tissue-injury theory is currently the favorite paradigm to investigate valve pathology. To the best of our knowledge, there are currently no in vivo valve injury models. There are few calcific aortic valve stenosis (AVS) models that develop hemodynamically significant stenosis. Here, we investigated the effect of direct mechanical injury on aortic valves in vivo and developed a novel mouse model of calcific AVS. Approach and Results—Aortic valve injury was created by inserting and moving a spring guidewire under echocardiographic guidance into the left ventricle of male C57/BL6 mice via right common carotid artery. Serial echocardiographic measurements revealed that aortic velocity was increased 1 week after injury and persistently increased until 16 weeks after injury. AVS mice showed a higher heart weight/body weight ratio and decreased left ventricular fractioning shortening 4 weeks after injury, compared with sham mice. We found remarkable proliferation of valve leaflets 4 weeks after injury. Proliferative valves showed increased production of reactive oxygen species and expression of inflammatory cytokines and osteochondrogenic factors. Alizarin red staining showed valvular calcification 12 weeks after injury. Conclusions—We report a novel calcific AVS model to support the response-to-tissue-injury theory. This model may be a valuable tool for analyzing the mechanism of AVS and assessing therapeutic options.

Impact of insulin resistance on silent and ongoing myocardial damage in normal subjects: the Takahata study.

Background. Insulin resistance (IR) is part of the metabolic syndrome (Mets) that develops after lifestyle changes and obesity. Although the association between Mets and myocardial injury is well known, the effect of IR on myocardial damage remains unclear. Methods and Results. We studied 2200 normal subjects who participated in a community-based health check in the town of Takahata in northern Japan. The presence of IR was assessed by homeostasis model assessment ratio, and the serum level of heart-type fatty acid binding protein (H-FABP) was measured as a maker of silent and ongoing myocardial damage. H-FABP levels were significantly higher in subjects with IR and Mets than in those without metabolic disorder regardless of gender. Multivariate logistic analysis showed that the presence of IR was independently associated with latent myocardial damage (odds ratio: 1.574, 95% confidence interval 1.1–2.3) similar to the presence of Mets. Conclusions. In a screening of healthy subjects, IR and Mets were similarly related to higher H-FABP levels, suggesting that there may be an asymptomatic population in the early stages of metabolic disorder that is exposed to myocardial damage and might be susceptible to silent heart failure.

The role of macrophage transcription factor MafB in atherosclerotic plaque stability

BACKGROUND AND AIMS Macrophage differentiation is associated with the development of atherosclerosis and plaque vulnerability and is regulated by transcription factor MafB. We previously reported that MafB attenuates macrophage apoptosis, which is associated with atherosclerotic plaque instability. The aim of this study was to elucidate the role of MafB in the progression of atherosclerotic plaque. METHODS We generated macrophage-specific dominant-negative (DN) MafB transgenic mice and intercrossed DN-MafB mice with apolipoprotein E (ApoE) knockout (KO) mice. RESULTS There was no significant difference in advanced atherosclerotic lesion area between DN-MafB/ApoE KO mice and littermate control ApoE KO mice 9 weeks after high-cholesterol diet. However, DN-MafB/ApoE KO mice showed significantly larger necrotic cores and lower collagen content in atherosclerotic plaques than ApoE KO mice. Although there was no difference in intraplaque macrophage infiltration and efferocytosis, DN-MafB/ApoE KO mice showed significantly more apoptotic macrophages at the plaque edges than did ApoE KO mice. Real-time PCR analysis revealed that peritoneal macrophages of DN-MafB/ApoE KO mice had a greater increase in matrix metalloproteinase-9 and mRNA expression of inflammatory/M1 macrophage markers (tissue necrosis factor-α, interleukin-6, CD11c, and p47phox) after lipopolysaccharide stimulation than those of ApoE KO mice. CONCLUSION Macrophage-specific inhibition of MafB may destabilize atherosclerotic plaques in advanced lesions.