[Show abstract][Hide abstract] ABSTRACT: Background
: Left atrial appendage (LAA) dysfunction predisposes patients with atrial fibrillation (AF) to cardioembolic stroke. Two-dimensional (2D) speckle tracking was reported to be useful for evaluating left atrial (LA) regional function, as well as left ventricular function. However, it remains unclear whether 2D speckle tracking is useful for evaluating LAA dysfunction. Therefore, we investigated whether decreased LA strain may predict LAA dysfunction and thrombus formation in patients with acute ischemic stroke.
We performed transthoracic and transesophageal echocardiography in 120 patients (83 males, mean age 72 ± 11 years) within 7 days of onset of an acute ischemic stroke. Longitudinal LA strain was evaluated using 2D speckle tracking imaging at each LA segment, and peak systolic strain was calculated by averaging the results for each segment.
Forty-eight patients had LAA dysfunction as defined by the presence of LAA thrombus and/or severe spontaneous echo contrast. LA peak systolic strain was significantly decreased in patients with LAA dysfunction compared to those without (32.3 ± 13.7% vs. 12.1 ± 7.2%, p < 0.0001). LA peak systolic strain was significantly correlated with LAA emptying flow velocity (r = 0.693, p < 0.0001). The optimum LA peak systolic strain cut off value for predicting LAA dysfunction was 19%. Multivariate logistic regression analysis showed that LA peak systolic strain was an independent predictor of LAA dysfunction (odds ratio 0.059, 95% confidence interval 0.018-0.146; p < 0.0001).
Decreased LA peak systolic strain was independently associated with LAA dysfunction in patients with acute ischemic stroke.
[Show abstract][Hide abstract] ABSTRACT: Aim: Pentraxin 3 (PTX3) is a novel marker for the primary local activation of innate immunity and inflammatory responses. Although clinical and experimental evidence suggests that PTX3 is associated with atherosclerosis, the relationship between PTX3 and vascular remodeling after wall injury remains to be determined. We investigated the effects of PTX3 on neointimal hyperplasia following wire vascular injury.Methods: PTX3 systemic knockout (PTX3-KO) mice and wild-type littermate (WT) mice were subjected to wire-mediated endovascular injury. At four weeks after wire-mediated injury, the areas of neointimal and medial hyperplasia were evaluated.Results: The PTX3-KO mice exhibited higher hyperplasia/media ratios than the WT mice after wire injury, and the degree of Mac-3-positive macrophage accumulation was significantly higher in the PTX3-KO mice than in the WT mice. Furthermore, the PTX3-KO mice showed a much greater increase in the number of PCNA-stained cells in the vascular wall than that observed in the WT mice.Conclusions: A deficiency of PTX3 results in deteriorated neointimal hyperplasia after vascular injury via the effects of macrophage accumulation and vascular smooth muscle cell proliferation and migration.
Journal of atherosclerosis and thrombosis 10/2014; · 2.77 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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.
Arteriosclerosis Thrombosis and Vascular Biology 12/2013; · 6.34 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Epicardial adipose tissue (EAT) surrounding the heart may contribute to the development of coronary artery disease (CAD) through its local secretion of adipocytokines. Although the quantity of EAT is associated with obesity and metabolic syndrome, the role of EAT in the development of CAD in non-obese patients remains to be determined.
This study included 41 patients with CAD who underwent coronary artery bypass graft surgery and 28 patients without CAD who underwent other cardiac surgery. EAT volume was measured by 64-slice multi-detector computed tomography before the surgery. We obtained pericardial fluid and epicardial and subcutaneous adipose tissue samples at the surgery. We investigated the relationship between EAT volume and adiponectin levels in pericardial fluid and incident CAD in patients with and without obesity (body mass index>25kg/m(2)).
There was no significant difference in EAT volume between obese patients with and without CAD (55.5±40.2mL vs. 40.1±19.7mL, p=0.323). However, EAT volume was significantly greater in non-obese patients with CAD compared to those without CAD (35.0±18.8mL vs. 15.7±11.0mL, p<0.001). Adiponectin concentrations in pericardial fluid were significantly lower in non-obese patients with CAD compared to those without CAD (2.7±2.0μg/mL vs. 4.3±3.7μg/mL, p=0.049), whereas the adiponectin levels were decreased in obese patients regardless of the presence of CAD. Non-obese patients with CAD had significantly larger size adipocytes in EAT but not subcutaneous adipose tissue compared to those without CAD. Multiple logistic regression analysis showed that increased EAT volume was independently associated with incident CAD in non-obese patients.
Increased EAT may play a crucial role in development of CAD through impairment of adiponectin secretion in non-obese patients.
Journal of Cardiology 11/2013; · 2.57 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Low-grade inflammation associated with heart failure (HF) is known to deteriorate cardioembolic stroke in patients with atrial fibrillation (AF). Little is known about the relationship between atrial endothelial impairment induced by innate immunity and thrombus formation. We examined whether atrial endothelial impairment through Toll-like receptor (TLR) 4 signaling causes atrial thrombogenesis. TLR4, heat shock protein 60, and vascular cell adhesion molecule (VCAM)-1 expression were higher in the atrium of AF patients who underwent valve replacement surgery with HF compared with those without it (p < 0.05). We created thoracic transverse aortic constriction (TAC) in TLR4 knock-out (KO) and wild-type (WT) mice. Atrial thrombosis was observed less frequently in TLR4 KO mice (4/15) than in WT mice (16/20) 4 weeks after TAC despite similar severity of heart failure. The decrease in endothelial nitric oxide synthase (eNOS) phosphorylation and increase in VCAM-1 and plasminogen activator inhibitor (PAI)-1 expression, observed in the atrium of WT mice following TAC, were significantly attenuated in TLR4 KO mice (p < 0.05). Nuclear factor-κB (NF-κB) activation after TAC was attenuated in TLR4 KO mice compared with WT mice. Activation of mitogen-activated protein kinase p38 (p38) after TAC was also attenuated in TLR4 KO mice (p < 0.05). Thus, increased VCAM-1 and PAI-1, and decreased eNOS phosphorylation through the TLR4/NFκB/p38 pathway, may be associated with atrial thrombogenesis in the heart failure mice model. Atrial endothelial impairment through the TLR4 signaling may play a role in atrial thrombogenesis in AF patients with HF.
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: -Renal dysfunction was reported to be closely associated with clinical outcomes in patients with chronic heart failure (CHF). Renal tubulointerstitial damage has been shown to be an important factor in the development of renal dysfunction as well as glomerular damage. However, it remains to be determined the impact of renal tubular damage on clinical outcomes in patients with CHF. METHODS AND RESULTS: -Urinary β2-microglobulin-creatinine ratio (UBCR) was measured in 315 patients with CHF. Renal tubular damage was defined as a UBCR ≥ 300 μg/g, as previously reported. Patients were prospectively followed for a median period of 1097 days. There were 91 cardiac events, including 16 cardiac deaths and 75 re-hospitalizations for worsening heart failure. Log10 UBCR was increased with worsening New York Heart Association (NYHA) functional class. Multivariate analysis revealed that renal tubular damage was an independent predictor of cardiac events. Kaplan-Meier analysis demonstrated that the rate of cardiac events was higher in patients with renal tubular damage compared to those without it. Patients were divided into 4 groups according to the presence of chronic kidney disease and renal tubular damage. The Cox proportional hazard analysis revealed that comorbidity of chronic kidney disease and renal tubular damage was associated with the highest risk for cardiac events compared to other groups. CONCLUSIONS: -Renal tubular damage was related to the severity of heart failure and was associated with poor outcomes in patients with CHF. Renal tubular damage could add clinical information to chronic kidney disease in patients with CHF.
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Left ventricular hypertrophy is enhanced by an inflammatory state and stimulation of various cytokines. Pentraxin 3 (PTX3) is rapidly produced in response to inflammatory signals, and high plasma PTX3 levels are seen in patients with heart failure. This study aimed to examine the influence of PTX3 on cardiac hypertrophy and left ventricular dysfunction with respect to pressure overload. METHODS AND RESULTS: PTX3 systemic knockout (PTX3-KO) mice, transgenic mice with cardiac-specific overexpression of PTX3 (PTX3-TG), and the respective wild-type (WT) littermate mice were subjected to transverse aortic constriction (TAC) or a sham operation. Cardiac PTX3 expression increased after TAC in WT mice. In vitro, hydrogen peroxide induced the expression of PTX3 in both cardiac myocytes and cardiac fibroblasts. Recombinant PTX3 phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2) in cardiac fibroblasts. Phosphorylation of cardiac ERK1/2 and nuclear factor kappa-B after TAC was attenuated in the PTX3-KO mice but was enhanced in the PTX3-TG mice compared with WT mice. Interleukin-6 and connective tissue growth factor production was lower in the PTX3-KO mice than in the WT mice, but this was augmented in the PTX3-TG mice than in the WT mice. Echocardiography revealed that adverse remodeling with left ventricular dysfunction, as well as with increased interstitial fibrosis, was enhanced in PTX3-TG mice, while these responses were suppressed in PTX3-KO mice. CONCLUSION: The local inflammatory mediator PTX3 directly modulates the hypertrophic response and ventricular dysfunction following an increased afterload.
PLoS ONE 01/2013; 8(1):e53133. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Renal dysfunction is reported to be associated with poor outcomes in patients with chronic heart failure (CHF). A recent study showed that acidic urine is related to chronic kidney disease, which is a risk factor for the development of CHF. However, it remains to be determined whether acidic urine is associated with poor outcomes in patients with CHF. We measured urine pH using dipsticks in 537 patients with CHF. Acidic urine was defined as urine pH ≤5.5. Patients were prospectively followed during a median follow-up period of 556 days. There were 145 cardiac events. Prevalence of acidic urine was increased with advancing stage of chronic kidney disease. Patients with acidic urine had a more severe New York Heart Association functional class compared with those with normal urine. In the multivariate Cox proportional hazard analysis, acidic urine was independently associated with poor outcomes in patients with CHF after adjustment of confounding factors. A Kaplan-Meier analysis demonstrated that the rate of cardiac events was higher in patients with acidic urine than in those with normal urine. The presence of acidic urine can reliably identify patients at high risk of future cardiac events in patients with CHF.
[Show abstract][Hide abstract] ABSTRACT: The association between ongoing myocardial damage and outcomes in patients who have received an implantable cardioverter-defibrillator (ICD) is unclear.
Consecutive patients with cardiomyopathy, who had received an ICD (n = 107, mean age 65 ± 11 years), were prospectively enrolled. Myocardial membrane injury (heart-type fatty acid binding protein [H-FABP] >4.3 ng/mL) and myofibrillar injury (troponin T >0.01 ng/mL) were defined using receiver operating characteristic curves. Patients were followed for a median of 33.6 months, to an end point of appropriate ICD shock or cardiac death. Myocardial membrane injury (45%) and myofibrillar injury (41%) were equally prevalent among patients with cardiomyopathy who had received ICDs. Appropriate ICD shocks or cardiac death occurred in 31% and 15% of patients, respectively. Multivariate Cox regression analysis showed that serum H-FABP levels >4.3 ng/mL, but not troponin T levels, were a significant independent prognostic factor for cardiac events (hazard ratio 5.502, 95% confidence interval 1.705-17.75, P = .004). Subgroup analysis revealed that measuring H-FABP levels was valuable for anticipating event-free survival among patients with ICDs who were receiving amiodarone. High H-FABP levels also predicted subsequent outcomes in patients who had received ICDs for primary or secondary prevention.
Evaluating myocardial damage using H-FABP may be a promising tool for predicting outcomes in patients with cardiomyopathy who have received ICDs.
Journal of cardiac failure 07/2012; 18(7):556-63. · 3.07 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Pregnancy-associated plasma protein A (PAPP-A) proteolyzes insulin-like growth factor (IGF)-binding proteins and thus increases IGF-1 bioactivity. PAPP-A has been reported to be involved in various pathophysiologic abnormalities; however, the clinical significance of PAPP-A has not been examined in cases of heart failure (HF). We hypothesized that PAPP-A levels might be correlated with the severity of HF.
PAPP-A and B-type natriuretic peptide (BNP) levels were measured in 262 subjects (182 HF patients and 80 control subjects). PAPP-A levels were higher in patients with HF than in control subjects and increased with advancing New York Heart Association functional class. There were 53 cardiac events during a mean follow-up period of 796 days. PAPP-A levels were higher in patients with cardiac events than in event-free patients. Patients were divided into 3 groups on the basis of their PAPP-A and BNP levels. Kaplan-Meier analysis demonstrated that the group with both high BNP with high PAPP-A had a significantly higher cardiac event rate than other groups.
Serum PAPP-A levels were related to the severity of HF and associated with a high risk for adverse cardiac events in HF patients, suggesting that PAPP-A might be involved in the pathogenesis of HF.
Journal of cardiac failure 10/2011; 17(10):819-26. · 3.07 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Cystatin C, a marker for early stage chronic kidney disease, has been shown to be involved in cardiovascular disease. The relationship between serum cystatin C levels and coronary vasospastic angina (VSA), however, remains to be elucidated. The aim of the present study was to investigate whether elevated cystatin C levels predict the incidence of VSA.
One hundred and ten patients were referred to hospital due to suspected VSA. VSA was evoked in 59 patients by a vasospasm provocation test with administration of acetylcholine into the coronary arteries. The patients with VSA had lower levels of high-density lipoprotein cholesterol and a higher history of cigarette smoking, higher levels of triglyceride, high-sensitivity C-reactive protein, and higher cystatin C levels compared with those without VSA. There were no differences in serum creatinine or estimated glomerular filtration rate between patients with and without VSA. Multivariate logistic regression indicated that history of smoking (odds ratio, 2.956 P<0.05) and cystatin C levels (odds ratio, 2.285; P<0.01) were independently associated with the incidence of VSA.
Elevated cystatin C levels were associated with higher incidence of VSA, suggesting that mild renal dysfunction may be implicated in the pathogenesis of coronary artery spasm.
[Show abstract][Hide abstract] ABSTRACT: DNA in the nucleus is one of the major targets of reactive oxygen species (ROS), and oxidative DNA damage has been implicated in the pathogenesis of chronic heart failure. 8-Hydroxy-2'-deoxyguanosine (8-OHdG) is produced from deoxyguanosine in DNA by ROS. The purpose of this present study was to examine the clinical significance of serum 8-OHdG levels in patients with heart failure.
We measured serum 8-OHdG levels in 230 patients with chronic heart failure and 42 control subjects without heart failure by sandwich enzyme-linked immunosorbent assay. Patients were prospectively followed during a median follow-up period of 472 days with the end points of cardiac death or progressive heart failure requiring re-hospitalization.
Serum 8-OHdG concentrations were higher in patients with heart failure than in control subjects (P < 0·001) and increased with advancing New York Heart Association (NYHA) functional class (P < 0·001). Normal upper limit of 8-OHdG level was determined as mean ± 2SD value from 42 control subjects (0·40 ng mL(-1)). Abnormally high serum 8-OHdG levels (> 0·40 ng mL(-1)) were observed in 21·2%, 43·1%, 42·6% and 69·4% through NYHA I to IV (P < 0·001). A total of 66 cardiac events occurred during a follow-up period, and Kaplan-Meier survival curves demonstrated that cardiac event rate was markedly higher in patients with high 8-OHdG levels than in those with normal 8-OHdG levels (62·4% vs. 29·6%, P = 0·0007).
Serum 8-OHdG levels provide important prognostic information for the risk stratification of patients with heart failure.
European Journal of Clinical Investigation 07/2011; 41(7):759-66. · 3.37 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Serum neopterin concentration was measured in 198 patients with chronic heart failure (CHF) and 62 control subjects by ELISA. Patients were prospectively followed during a median follow-up period of 745 days with end points of cardiac death or re-hospitalization due to progressive heart failure. Serum concentration of neopterin increased with advancing New York Heart Association (NYHA) functional class (P<0.001). High neopterin group had a significantly higher incidence of cardiac events than low neopterin group (P<0.0001). In the multivariate Cox analysis, serum neopterin concentration was an independent risk factor for cardiac events (hazard ratio 1.70, 95%CI 1.16-2.50, P=0.0068). Serum neopterin concentration is a novel prognostic marker for CHF.
International journal of cardiology 11/2010; 145(2):318. · 6.18 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Human cartilage glycoprotein-39 (YKL-40), a novel inflammatory marker, is secreted into circulation by macrophages, neutrophils, chondrocytes, vascular smooth muscle cells and cancer cells. Circulating levels of YKL-40 are related to the degree of inflammation, tissue remodeling, fibrosis, and cancer progression.
We examined serum YKL-40 levels in 121 patients with chronic heart failure (CHF) and 39 control subjects. The patients were followed up to register cardiac events for a mean of 720 days. Serum YKL-40 levels were measured by sandwich enzyme-linked immunoassay. Serum YKL-40 was significantly higher in New York Heart Association (NYHA) Class III/IV patients than control subjects and NYHA Class I/II patients (P < .0001). Serum YKL-40 was also higher in patients with cardiac events than in event-free patients (P = .0023). Cutoff value of YKL-40 was determined by receiver operating characteristic curve analysis. Kaplan-Meier analysis demonstrated that high level of YKL-40 was associated with higher rates of cardiac events than low levels of YKL-40 (P = .003). The multivariate Cox hazard analysis demonstrated that serum YKL-40 level was an independent prognostic factor of cardiac events (hazard ratio 2.085, 95% confidence interval 1.233-3.499, P < .0048).
Serum YKL-40, a new marker of inflammation, was increased in CHF, and YKL-40 detected high risk patients for adverse outcomes in CHF.
Journal of cardiac failure 11/2010; 16(11):873-9. · 3.07 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Iodine-123-metaiodobenzylguanidine ((123)I-MIBG) has been used to assess the function of the cardiac sympathetic nervous system in patients with chronic heart failure (HF). The usefulness of (123)I-MIBG imaging for evaluating patients with heart failure with preserved ejection fraction (HFPEF) has not been established.
We performed (123)I-MIBG scintigraphy and echocardiography and measured the plasma brain natriuretic peptide (BNP) levels of 117 consecutive HF patients (64 men, mean age 66 ± 14 years) with a left ventricular ejection fraction (LVEF) of ≥50% who were admitted to our hospital. Patients were divided into 2 groups according to the New York Heart Association (NYHA) functional class.
The (123)I-MIBG delayed heart-to-mediastinum (H/M) ratio was significantly lower, and the washout rate (WR) was higher in patients with HFPEF with advanced NYHA functional class (NYHA functional class I and II vs. III: 1.90 ± 0.34 vs. 1.49 ± 0.32, p < 0.0001; 25.9 ± 13.4 vs. 46.9 ± 16.3%, p < 0.0001, respectively). On the other hand, the (123)I-MIBG WR was not correlated with LVEF and had a weak correlation with plasma BNP levels (R = 0.207, p = 0.0346). Moreover, patients with a high (123)I-MIBG WR showed a poor clinical outcome (p = 0.0033).
(123)I-MIBG imaging provides independent prognostic information in patients with HFPEF.
Annals of Nuclear Medicine 11/2010; 24(9):679-86. · 1.41 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Midkine, a heparin-binding growth factor, has various functions such as migration of inflammatory cell and anti-apoptotic effect. Invasion of inflammatory cell and cardiomyocyte apoptosis are involved in development and progression of heart failure (HF). However, the relationship between midkine and HF has not been previously examined. Therefore, we examined clinical significance of serum midkine levels to determine the prognosis of HF patients.
Serum levels of midkine were measured at admission in 216 consecutive patients hospitalized for HF and 60 control subjects. Patients were prospectively followed during a mean follow-up period of 653 +/- 375 days with the end points of cardiac death and progressive HF requiring rehospitalization. Serum concentrations of midkine were significantly higher in patients with HF than in controls. Patients with cardiac events had significantly higher concentrations of midkine than those without cardiac events. Kaplan-Meier analysis revealed that cardiac event rates increased markedly as midkine levels rose. Furthermore in the multivariate analysis, after adjustment for age, gender ,and complications, midkine was the independent predictor of cardiac events.
Serum midkine levels are increased in HF patients, and midkine is a novel marker for risk stratifying HF patients.
Journal of cardiac failure 04/2010; 16(4):308-13. · 3.07 Impact Factor