Usefulness of Inter-Hospital Heart Team Conference Based Collaborative Outpatient Cardiac Rehabilitation in Patients with Cardiovascular Disease.

An inter-hospital heart team conference based collaborative follow-up (FU) may facilitate outpatient cardiac rehabilitation (CR) programs, especially in hospitals without an outpatient CR center. Consecutive 145 patients with cardiovascular disease who received inpatient treatment at Yamagata University Hospital were divided into collaborative (n = 76) and same-hospital (n = 69) FU groups. In the collaborative FU group, patients received outpatient care at a university hospital and outpatient CR at different hospitals. In the same-hospital FU group, patients received outpatient care and outpatient CR at the same hospital other than the university hospital. The collaborative FU group held monthly 60-minute inter-hospital heart team conferences with CR specialists. No cardiovascular accidents occurred during the outpatient CR program in either group. Peak oxygen uptake VO2, anaerobic threshold, brain natriuretic peptide level, and left ventricular ejection fraction significantly improved in both groups. Kaplan-Meier analysis revealed no significant difference in prognosis between the collaborative and same-hospital FU groups (P = 0.246). Of the patients who had collaborative CR programs, 29 (38.2%) patients (37 consultations) were discussed at an inter-hospital heart team conference. Eighteen (48.6%) consultations were for issues related to continuing outpatient CR programs. Collaborative FU was as useful as same-hospital FU in terms of safety, efficacy, and prognosis in patients with cardiovascular disease. We conclude that regular inter-hospital heart team conferences are useful for facilitating collaboration among outpatient CR programs.

Comparison between febuxostat and allopurinol uric acid-lowering therapy in patients with chronic heart failure and hyperuricemia: a multicenter randomized controlled trial.

OBJECTIVE: Heart failure (HF) is a common and highly morbid cardiovascular disorder. Oxidative stress worsens HF, and uric acid (UA) is a useful oxidative stress marker. The novel anti-hyperuricemic drug febuxostat is a potent non-purine selective xanthine oxidase inhibitor. The present study examined the UA-lowering and prognostic effects of febuxostat in patients with HF compared with conventional allopurinol. METHODS: This multicenter, randomized trial included 263 patients with chronic HF who were randomly assigned to two groups and received allopurinol or febuxostat (UA >7.0 mg/dL). All patients were followed up for 3 years after enrollment. RESULTS: There were no significant differences in baseline clinical characteristics between the two groups. The UA level was significantly decreased after 3 years of drug administration compared with the baseline in both groups. Urine levels of the oxidative stress marker 8-hydroxy-2'-deoxyguanosine were lower in the febuxostat group than in the allopurinol group (11.0 ± 9.6 vs. 22.9 ± 15.9 ng/mL), and the rate of patients free from hospitalization due to worsening HF tended to be higher in the febuxostat group than in the allopurinol group (89.0% vs. 83.0%). CONCLUSIONS: Febuxostat is potentially more effective than allopurinol for treating patients with chronic HF and hyperuricemia.This study was registered in the University Hospital Medical Information Network Clinical Trials Registry (https://www.umin.ac.jp/ctr/; ID: 000009817).

Difference of clinical course after catheter ablation of atrioventricular nodal reentrant tachycardia between younger and older patients: atrial vulnerability predicts new onset of atrial fibrillation.

BACKGROUND: The aim of this study was to compare the long-term procedural outcomes, the stability of atrioventricular conduction, and the new onset of atrial fibrillation (AF), after ablation of atrioventricular nodal reentrant tachycardia (AVNRT). METHODS AND RESULTS: Consecutive patients with AVNRT (n=109), who underwent slow-pathway ablation, were divided into two groups based on the median age of the studied patients: the younger group aged <55 years and the older group aged ≥55 years. During a mean follow-up period of 60.6 months, the rate of change in the PR interval from before ablation to follow-up was significantly greater in older patients compared with younger patients. However, there was no delayed-onset high-degree AV block during follow-up in either group. No patients in the younger group suffered from persistent AF, whereas persistent AF occurred in 5/54 (9.3%) older patients. Multivariate Cox analysis revealed that atrial vulnerability, with induction of AF during the electrophysiological study, was the only predictor of the development of AF (Hazard ratio: 13.9, 95% confidence interval: 1.62-119.2, p<0.01). CONCLUSION: Slow-pathway ablation of AVNRT is a reliable strategy even in older patients. However, physicians should consider regular long-term follow-up of older patients with atrial vulnerability, in order to assess the subsequent development of AF.

Persistently increased serum concentration of heart-type fatty acid-binding protein predicts adverse clinical outcomes in patients with chronic heart failure.

BACKGROUND: Heart-type fatty acid-binding protein (H-FABP) is a small cytosolic protein that is released into the circulation when the myocardium is injured. This study examined whether serial measurement of the H-FABP level provides additional prognostic information. METHODS AND RESULTS: Serum H-FABP levels were measured in 113 consecutive chronic heart failure (CHF) patients at both admission and discharge. The following 3 patterns of changes were identified. In 41 patients, H-FABP levels (<4.3 ng/ml) at both admission and discharge were normal (Group 1). The remaining 72 patients had high initial H-FABP levels (> or =4.3 ng/ml) at admission, and in 21 of them (29%), H-FABP decreased to the normal range at discharge (Group 2), whereas 51 had persistently high H-FABP levels despite improvement in symptoms and signs of CHF (Group 3). There were 33 cardiac events (29%) during the follow-up period, and Group 3 had significantly higher cardiac event rates than Groups 1 and 2 (p=0.0002). Group 3 had the highest cardiac risk among the groups (hazard ratio 5.68, p=0.012). CONCLUSION: Serial measurement of the H-FABP level is a new monitoring tool that provides information to guide optimal therapy and management of CHF patients.

Serum carboxy-terminal telopeptide of type I collagen (ICTP) predicts cardiac events in chronic heart failure patients with preserved left ventricular systolic function.

BACKGROUND: Clinical markers to predict adverse outcome have not yet been established for patients with preserved left ventricular (LV) systolic function. The present study was designed to examine whether carboxy-terminal telopeptide of type I collagen (ICTP), a marker of collagen degradation, is useful for determining the prognosis of such patients. METHODS AND RESULTS: Serum levels of ICTP were measured at admission in 156 consecutive patients hospitalized for chronic heart failure (CHF). Patients were divided into 2 groups based on the LV ejection fraction (LVEF): reduced LV systolic function group (LVEF <50%, n=92) and preserved LV systolic function group (LVEF > or =50%, n=64). In preserved LV systolic function group, cardiac event-free rates were significantly lower in high ICTP group than in low ICTP group (p<0.001). The area under the receiver operating characteristic curve of ICTP in the preserved LV systolic function group was markedly larger than that in the reduced LV systolic function group. Cox multivariate analysis also revealed that ICTP was an independent predictor of cardiac events in the preserved LV systolic function group. CONCLUSION: Serum ICTP level is highly reliable for risk stratifying CHF patients with preserved LV systolic function.

High serum level of pentosidine, an advanced glycation end product (AGE), is a risk factor of patients with heart failure.

BACKGROUND: Pentosidine, one of the advanced glycation end products (AGE), is generated by nonenzymatic glycation and oxidation of proteins. The receptor of AGE (RAGE) is expressed in a variety of tissue, and interaction of AGE with RAGE induces oxidative stress and activation of intracellular signaling, causing production of cytokines and mediators of inflammation. We investigated whether serum pentosidine is a risk factor for heart failure. METHODS AND RESULTS: Serum pentosidine concentration was measured in 141 patients with heart failure and 18 control subjects by a competitive enzyme-linked immunosorbent assay. Patients were prospectively followed during a median follow-up period of 479 days with end points of cardiac death or rehospitalization. Serum concentration of pentosidine was significantly higher in New York Heart Association (NYHA) Class III/IV patients than in NYHA class I/II patients (P < .0001). Serum pentosidine was also higher in patients with cardiac events than in event-free patients (P < .001). In the univariate Cox proportional hazard analysis, age, NYHA class, pentosidine, creatinine, uric acid, B-type natriuretic peptide, left ventricular end-systolic volume, and left ventricular mass were significant risk factors to predict cardiac events. In the multivariate Cox analysis, serum pentosidine concentration was an independent risk factor for cardiac events (hazard ratio 1.88, 95% confidence interval 1.23-2.69, P = .002). The highest 4th quartile of pentosidine was associated with the highest risk of cardiac events (4.52-fold). CONCLUSIONS: Serum pentosidine concentration is an independent prognostic factor for heart failure, and this new marker may be useful for risk stratification of patients with heart failure. Patients were divided into 4 groups based on the serum pentosidine levels.

Cardiac sympathetic denervation and ongoing myocardial damage for prognosis in early stages of heart failure.

BACKGROUND: Iodine-123-metaiodobenzylguanidine ((123)I-MIBG) can assess cardiac sympathetic nervous function. Heart-type fatty acid binding protein (H-FABP) has been used as a marker of ongoing myocardial damage. The prognostic value of combination (123)I-MIBG imaging and H-FABP in heart failure is unknown. METHODS AND RESULTS: We prospectively enrolled consecutive 104 patients with heart failure in whom we quantified (123)I-MIBG scintigraphy, simultaneously measured serum H-FABP and plasma brain natriuretic peptide (BNP) levels, and analyzed clinical outcomes. The multivariate Cox regression analysis revealed that augmented H-FABP level and decreased heart to mediastinum ratio of (123)I-MIBG at 240 minutes (delayed H/M ratio), but not BNP, were the independent predictors for cardiac events. The cutoff values for H-FABP and delayed H/M ratio were determined from the receiver operating characteristic curves as 5.2 ng/mL for H-FABP and 1.73 for delayed H/M ratio. The cardiac event rate was markedly higher in patients with both H-FABP and delayed H/M ratio of (123)I-MIBG was abnormal. Conversely, no cardiac events occurred in patients with both H-FABP level and delayed H/M ratio were normal. CONCLUSION: H-FABP adds independent prognostic information to delayed H/M ratio of (123)I-MIBG imaging, and the combination of these approaches may improve the accuracy of prognostic determination in heart failure.

Heart-type fatty acid-binding protein is more sensitive than troponin T to detect the ongoing myocardial damage in chronic heart failure patients.

BACKGROUND: Heart-type fatty acid-binding protein (H-FABP) is a small cytosolic protein and released into the circulation when the myocardium is injured. Previous studies have demonstrated that both H-FABP and troponin T (TnT) are detectable in venous blood samples in chronic heart failure (CHF) patients, suggesting the presence of ongoing myocardial damage (OMD). We hypothesized that a cytosolic marker (H-FABP) is more sensitive than a myofibrillar component (TnT) in the detection of OMD in CHF. METHODS AND RESULTS: We measured serum H-FABP and TnT levels in 126 consecutive CHF patients at admission, and patients were followed-up with a mean period of 474 +/- 328 days. Cutoff values for H-FABP (4.3 ng/mL) and TnT (0.01 ng/mL) were determined from previous studies. Positive rate of H-FABP was higher than that of TnT in all CHF patients (46% [58/126] versus 26% [33/126], P < .0001), and in severe CHF (New York Heart Association III/IV) patients (69% [34/49] versus 47% [23/49], P = .0121). There were 27 cardiac events during a follow-up period. In patients with cardiac events, H-FABP was more frequently detected than TnT (88% [24/27] versus 44% [12/27], P = .0103). There were 33 patients with positive H-FABP among 93 patients with negative TnT. Those patients had more severe New York Heart Association class, higher levels of brain natriuretic peptide, and higher rates of cardiac events (36% versus 5%, P < .0001) compared with those both H-FABP and TnT were negative. Kaplan-Meier analysis demonstrated that in patients with negative TnT, positive H-FABP group had higher risk for cardiac events than negative H-FABP group (P < .0001). A multivariate analysis with Cox proportional hazard model showed that H-FABP was the only independent predictor of cardiac events (hazard ratio 15.677, P = .0001). The area under the receiver operating characteristic curve was larger for H-FABP than for TnT (0.779 versus 0.581; P = .009), suggesting that H-FABP had greater predictive capacity for cardiac events than TnT. CONCLUSIONS: H-FABP was more sensitive to detect OMD and could identify patients at high risk more effectively than TnT.

Serum resistin is associated with high risk in patients with congestive heart failure--a novel link between metabolic signals and heart failure.

BACKGROUND: Resistin is derived from fat tissue in rodents, and serum levels are elevated in animal models of obesity and insulin resistance. Recent studies have reported that resistin is correlated with markers of inflammation and oxidative stress and is predictive of coronary atherosclerosis in humans. However, clinical significance of serum resistin has not been examined in heart failure. Therefore, the purpose of this study was to examine whether: (1) resistin is correlated with the severity of heart failure; and (2) resistin can predict clinical outcomes of patients with heart failure. METHODS AND RESULTS: Serum levels of resistin in 126 patients hospitalized for heart failure and 18 control subjects were measured. The patients were followed up with end-points of cardiac death and re-hospitalization caused by worsening of heart failure. The serum resistin level was higher in patients with heart failure than in control subjects and increased with advancing New York Heart Association functional class. The normal upper limit of the resistin level was determined as the mean +2 standard deviation value of control subjects (14.1 ng/ml). In heart failure patients, the cardiac event rate was higher in patients with a high resistin level than in those with a normal level. Among age, body mass index, serum levels of resistin, brain natriuretic peptide, loop diuretics selected by the univariate Cox regression hazard analysis, age and resistin were significant predictors of future cardiac events by multivariate Cox analysis. CONCLUSION: Serum resistin was related to the severity of heart failure and associated with a high risk for adverse cardiac events in patients with heart failure.

Hyperuricemia associated with high cardiac event rates in the elderly with chronic heart failure.

OBJECTIVES: Congestive heart failure (CHF) is the major cause of death and hospitalization in the elderly population. Simple markers that can be measured anywhere at low cost are necessary to identify patients at high risk. Recent studies have reported that hyperuricemia is a prognostic marker for CHF. However, it is not yet known whether serum levels of uric acid may provide prognostic information in the elderly population. Therefore, this study tried to identify the clinical characteristics of elderly CHF patients (+/-70 years) in our institution and to evaluate whether uric acid levels can effectively estimate the prognosis for elderly CHF patients. METHODS AND RESULTS: Uric acid levels were analyzed in 247 CHF patients, and patients were followed up for 451 +/- 235 days (mean +/- SD). Elderly CHF patients aged > or =70 years (123 patients) had higher rate of hypertension, lower current smoking rate and higher uric acid levels than those aged < 70 years (124 patients). There were 72 cardiac events including cardiac deaths and readmissions for worsening CHF. Multivariate analysis with the Cox proportional hazard model showed that uric acid was the only independent predictor of cardiac events (hazard ratio 1.544, 95% confidence interval 1.215-2.582, p < 0.0001) in the elderly with CHF. The highest quartile of uric acid level was associated with the highest risk of cardiac events (a 4.45-fold compared to the lowest quartile). Kaplan-Meier analysis revealed that uric acid levels effectively risk stratified elderly CHF patients for cardiac events. CONCLUSIONS: These findings suggest that measurement of uric acid levels in elderly CHF patients may add valuable prognostic information to predict cardiac events.

Central role of endogenous Toll-like receptor-2 activation in regulating inflammation, reactive oxygen species production, and subsequent neointimal formation after vascular injury.

BACKGROUND: It is now evident that inflammation after vascular injury has significant impact on the restenosis after revascularization procedures such as angioplasty, stenting, and bypass grafting. However, the mechanisms that regulate inflammation and repair after vascular injury are incompletely understood. Here, we report that vascular injury-mediated cytokine expression, reactive oxygen species (ROS) production, as well as subsequent neointimal formation requires Toll-like receptor-2 (TLR-2) mediated signaling pathway in vivo. METHODS AND RESULTS: Vascular injury was induced by cuff-placement around the femoral artery in non-transgenic littermates (NLC) and TLR-2 knockout (TLR-2KO) mice. After cuff-placement in NLC mice, expression of TLR-2 was significantly increased in both smooth muscle medial layer and adventitia. Interestingly, we found that inflammatory genes expression such as tumor necrosis factor-alpha, interleukin-1beta (IL-1beta), IL-6, and monocyte chemoattractant protein-1 were markedly decreased in TLR-2KO mice compared with NLC mice. In addition, ROS production after vascular injury was attenuated in TLR-2KO mice compared with NLC mice. Since we observed the significant role of endogenous TLR-2 activation in regulating inflammatory responses and ROS production after vascular injury, we determined whether inhibition of endogenous TLR-2 activation can inhibit neointimal proliferation after vascular injury. Neointimal hyperplasia was markedly suppressed in TLR-2KO mice compared with WT mice at both 2 and 4 weeks after vascular injury. CONCLUSIONS: These findings suggested that endogenous TLR-2 activation might play a central role in the regulation of vascular inflammation as well as subsequent neointimal formation in injured vessels.

Cardiac-specific overexpression of diacylglycerol kinase zeta prevents Gq protein-coupled receptor agonist-induced cardiac hypertrophy in transgenic mice.

BACKGROUND: Diacylglycerol is a lipid second messenger that accumulates in cardiomyocytes when stimulated by Gqalpha protein-coupled receptor (GPCR) agonists such as angiotensin II, phenylephrine, and others. Diacylglycerol functions as a potent activator of protein kinase C (PKC) and is catalyzed by diacylglycerol kinase (DGK) to form phosphatidic acid and inactivated. However, the functional roles of DGK have not been previously examined in the heart. We hypothesized that DGK might prevent GPCR agonist-induced activation of diacylglycerol downstream signaling cascades and subsequent cardiac hypertrophy. METHODS AND RESULTS: To test this hypothesis, we generated transgenic (DGKzeta-TG) mice with cardiac-specific overexpression of DGKzeta. There were no differences in heart size and heart weight between DGKzeta-TG and wild-type littermate mice. The left ventricular function was normal in DGKzeta-TG mice. Continuous administration of subpressor doses of angiotensin II and phenylephrine caused PKC translocation, gene induction of atrial natriuretic factor, and subsequent cardiac hypertrophy in WT mice. However, in DGKzeta-TG mice, neither translocation of PKC nor upregulation of atrial natriuretic factor gene expression was observed after angiotensin II and phenylephrine infusion. Furthermore, in DGKzeta-TG mice, angiotensin II and phenylephrine failed to increase cross-sectional cardiomyocyte areas and heart to body weight ratios. Phenylephrine-induced increases in myocardial diacylglycerol levels were completely blocked in DGKzeta-TG mouse hearts, suggesting that DGKzeta regulated PKC activity by controlling cellular diacylglycerol levels. CONCLUSIONS: These results demonstrated the first evidence that DGKzeta negatively regulated the hypertrophic signaling cascade and resultant cardiac hypertrophy in response to GPCR agonists without detectable adverse effects in in vivo hearts.

Ongoing myocardial damage relates to cardiac sympathetic nervous disintegrity in patients with heart failure.

UNLABELLED: Iodine-123-metaiodobenzylguanidine (123I-MIBG) has been used to assess the integrity and function of the cardiac sympathetic nervous system in patients with heart failure. Heart-type fatty acid binding protein (H-FABP) is released into the circulation when the myocardium is injured, and H-FABP has been recently used as a novel marker for the diagnosis of ongoing myocardial damage. OBJECTIVE: The aim of the present study was to compare cardiac sympathetic nervous activity assessed by 123I-MIBG imaging with serum levels of H-FABP in patients with heart failure. METHODS: Fifty patients with chronic heart failure were studied. 123I-MIBG imaging was carried out at 30 min (early) and 240 min (delayed) after the tracer injection. We measured serum levels of H-FABP using a sandwich enzyme linked immunosorbent assay. RESULTS: Heart to mediastinum (H/M) ratios of 123I-MIBG decreased and washout rate increased with higher New York Heart Association (NYHA) functional class. H-FABP, norepinephrine and brain natriuretic peptide (BNP) levels increased as the severity of NYHA class advanced. Delayed H/M ratio was significantly correlated with H-FABP (r = -0.296, p = 0.029) and BNP (r = -0.335, p = 0.0213). Myocardial washout rate of 123I-MIBG was also correlated with H-FABP (r = 0.469, p < 0.001), norepinephrine (r = 0.433, p = 0.005), and BNP (r = 0.465, p = 0.001). CONCLUSIONS: These data suggest that cardiac sympathetic nervous activation was associated with ongoing cardiomyocyte damage characterized by an elevated serum level of H-FABP in patients with heart failure. 123I-MIBG imaging is an appropriate approach to evaluate non-invasively not only cardiac sympathetic nervous activity, but also latent ongoing myocardial damage in the failing heart.

Cystatin C, a novel measure of renal function, is an independent predictor of cardiac events in patients with heart failure.

BACKGROUND: Cystatin C, a novel endogenous marker of glomerular filtration rate, has been reported as more sensitive to detect renal insufficiency than creatinine. The purpose of the present study was to examine the clinical significance of serum cystatin C level in patients with mild to moderate heart failure. METHODS AND RESULTS: Serum levels of cystatin C were measured by an enzyme immunoassay in 140 patients with heart failure and 64 control subjects without heart failure. Patients were prospectively followed during a median follow-up period of 480 days, with the end points of cardiac death and progressive heart failure requiring rehospitalization. Serum levels of cystatin C were higher in patients with heart failure than in control subjects (1.14 +/- 0.60 ng/mL versus 0.72 +/- 0.14 ng/mL, P < .001). The Cox multivariate proportional hazard analysis revealed that a change of 1 standard deviation (SD) in cystatin C level was the one of independent predictor for cardiac events (hazard ratio, 1.94; 95% confidence interval, 1.29-6.64; P < .01). The cardiac event rate was markedly higher in patients with elevated cystatin C level (> or =1.0 ng/mL) than in those with normal level (< or =1.0 ng/mL) (38.7% versus 10.3%, P < 0.001). Furthermore in patients with normal creatinine levels (n = 91), the cardiac event rate was similarly higher in patients with elevated cystatin C than in those with normal levels (29.2% versus 7.5%, P = .002). CONCLUSION: Elevation of serum cystatin C, a new marker of renal function, provides promising prognostic information for clinical outcome in patients with mild to moderate heart failure.

Serum heart-type fatty acid binding protein predicts cardiac events in elderly patients with chronic heart failure.

BACKGROUND AND OBJECTIVES: Heart-type fatty acid binding protein (H-FABP) is released into the circulation from the damaged myocardium of patients with severe chronic heart failure. Chronic heart failure is the most frequent cause of death and disability in the elderly. However, there are no data for the prognostic value of H-FABP in the elderly population. This study investigated whether H-FABP can effectively predict the prognosis in elderly patients (> or = 70 years) with chronic heart failure. METHODS: Serum H-FABP levels were measured in 90 chronic heart failure patients > or =70 years old (mean age 77 +/- 4 years, range 70-92 years), and patients were followed-up for 421 +/- 326 days. RESULTS: There were 35 cardiac events (38.9%) including cardiac deaths and readmissions for worsening chronic heart failure. Multivariate analysis with the Cox proportional hazard model showed that H-FABP was the only independent predictor of cardiac events (chi2 = 6.640, p = 0.0100). Kaplan-Meier analysis revealed that H-FABP effectively risk stratified elderly patients with chronic heart failure for cardiac events. CONCLUSIONS: These findings suggest that H-FABP is a reliable marker for prognosis in elderly patients with chronic heart failure.

Combination of heart-type fatty acid binding protein and brain natriuretic peptide can reliably risk stratify patients hospitalized for chronic heart failure.

BACKGROUND: The aim of the present study was to prospectively study whether a combination of markers for myocardial cell injury and left ventricular overload at admission can reliably risk stratify patients hospitalized for chronic heart failure (CHF). METHODS AND RESULTS: Serum concentrations of heart-type fatty acid binding protein (H-FABP) and plasma concentrations of brain natriuretic peptide (BNP) were measured at admission in 186 consecutive patients hospitalized for CHF. During a mean follow-up period of 534+/-350 days, there were 44 cardiac events, including 16 cardiac deaths and 28 readmissions for worsening heart failure. Normal upper limits for H-FABP and BNP values were determined from the receiver operating characteristic curves (4.3 ng/ml for H-FABP and 200 pg/ml for BNP). A stepwise Cox regression analysis demonstrated that high H-FABP (hazard ratio 5.416, p = 0.0002) and high BNP (hazard ratio 2.411, p = 0.0463) were independent predictors of cardiac events. High concentrations of both H-FABP and BNP at admission were associated with the highest incidence of cardiac mortality and cardiac events. Kaplan-Meier analysis also showed that the combination of H-FABP and BNP concentrations could reliably stratify patients for cardiac events. CONCLUSION: Combined measurement of H-FABP and BNP concentrations at admission may be a highly reliable evaluation for risk stratifying patients hospitalized for CHF.

Adenovirus-mediated overexpression of diacylglycerol kinase-zeta inhibits endothelin-1-induced cardiomyocyte hypertrophy.

BACKGROUND: Diacylglycerol (DAG) is a lipid second messenger that transiently accumulates in cells stimulated by endothelin-1 (ET-1) and other Galphaq protein-coupled receptor agonists. Diacylglycerol kinase (DGK) is thought to be an enzyme that controls the cellular levels of DAG by converting it to phosphatidic acid; however, the functional role of DGK has not been examined in cardiomyocytes. Because DGK inactivates DAG, a strong activator of protein kinase C (PKC), we hypothesized that DGK inhibited ET-1-induced activation of a DAG-PKC signaling cascade and subsequent cardiomyocyte hypertrophy. METHODS AND RESULTS: Real-time reverse transcription-polymerase chain reaction demonstrated a significant increase of DGK-zeta mRNA by ET-1 in cardiomyocytes. To determine the functional role of DGK-zeta, we overexpressed DGK-zeta in cardiomyocytes using a recombinant adenovirus encoding rat DGK-zeta (Ad-DGKzeta). ET-1-induced translocation of PKC-epsilon was blocked by Ad-DGKzeta (P<0.01). Ad-DGKzeta also inhibited ET-1-induced activation of extracellular signal-regulated kinase (P<0.01). Luciferase reporter assay revealed that ET-1-mediated increase of activator protein-1 (AP1) DNA-binding activity was significantly inhibited by DGK-zeta (P<0.01). In cardiomyocytes transfected with DGK-zeta, ET-1 failed to cause gene induction of atrial natriuretic factor, increases in [3H]-leucine uptake, and increases in cardiomyocyte surface area. CONCLUSIONS: We demonstrated for the first time that DGK-zeta blocked ET-1-induced activation of the PKC-epsilon-ERK-AP1 signaling pathway, atrial natriuretic factor gene induction, and resultant cardiomyocyte hypertrophy. DGK-zeta might act as a negative regulator of hypertrophic program in response to ET-1, possibly by controlling cellular DAG levels.

Prognostic value of elevated circulating heart-type fatty acid binding protein in patients with congestive heart failure.

BACKGROUND: Heart-type fatty acid binding protein (H-FABP) is released into the circulation when the myocardium is injured and is a novel marker for the diagnosis of acute myocardial infarction. The purpose of the present study was to examine the clinical significance of increased serum H-FABP levels in patients with congestive heart failure. METHODS AND RESULTS: Serum levels of H-FABP were measured in 179 patients admitted with congestive heart failure and 20 age-matched normal controls by using a sandwich enzyme-linked immunosorbent assay. Patients were prospectively followed during a mean follow-up period of 20 months with the end points of cardiac death and progressive heart failure requiring rehospitalization. Serum levels of H-FABP were higher in patients with congestive heart failure than in control subjects (5.7 +/- 4.8 ng/mL versus 2.7 +/- 0.8 ng/mL, P < .01) and increased with advancing NYHA class (P < .01). The cardiac event rate was markedly higher in patients with elevated H-FABP levels than in those with normal levels (43% versus 7%, P < .0001). Furthermore, the Cox multivariate proportional hazard analysis revealed that the elevated H-FABP level was the only independent predictor for cardiac events (chi2= 7.397, P < .01). CONCLUSIONS: Elevation of H-FABP indicates latent and ongoing cardiomyocyte damage and identifies patients at high risk for future cardiac events in congestive heart failure.

Modulation of doxorubicin-induced cardiac dysfunction in toll-like receptor-2-knockout mice.

BACKGROUND: Toll-like receptors (TLRs) are members of the interleukin-1 receptor family and are involved in the responsiveness to pathogen-associated molecular patterns. Recent studies have demonstrated that TLRs are activated by endogenous signals, such as heat shock proteins and oxidative stress, which may contribute to congestive heart failure. Oxidative stress is one of the major factors in doxorubicin (Dox)-induced cardiac dysfunction. Thus, we hypothesized that TLRs contribute to the pathogenesis of Dox-induced cardiac dysfunction. METHODS AND RESULTS: Cardiac dysfunction was induced by a single injection of Dox (20 mg/kg IP) into wild-type (WT) mice and TLR-2-knockout (KO) mice. Five days after Dox injection, left ventricular dimension at end-diastole was smaller and fractional shortening was higher in KO mice compared with WT mice (P<0.01). Nuclear factor-kappaB activation and production of proinflammatory cytokines after Dox were suppressed in KO mice compared with WT mice (P<0.01). The numbers of TUNEL-positive nuclei and Dox-induced caspase-3 activation were less in KO mice than in WT mice (P<0.01). Survival rate was significantly higher in KO mice than in WT mice 10 days after Dox injection (46% vs 11%, P<0.05). CONCLUSIONS: These findings suggest that TLR-2 may play a role in the regulation of inflammatory and apoptotic mediators in the heart after Dox administration.