Phosphoglucomutase activity as a novel biomarker in patients with acute myocardial infarction.

BACKGROUND: Phosphoglucomutase (PGM), a key enzyme in cellular glucose utilization and energy homeostasis, has been reported to show a relationship with oxidative stress. However, the clinical importance of PGM activity has not been investigated in patients with ischemic heart disease (IHD). The aim of the present pilot study was to clarify whether PGM activity has potential as a cardiovascular risk predictor in patients with IHD. METHODS AND RESULTS: The levels of serum PGM activity in 237 patients with IHD (63 patients with acute myocardial infarction (AMI) and 174 patients with stable effort angina pectoris (EAP)) were evaluated. PGM activity was compared with levels of various myocardial, thrombosis, and inflammatory biomarkers on admission. PGM activity in the AMI group was significantly increased relative to that in the EAP group on admission (AMI, 55.5 µmol·min(-1)·L(-1) (U/L); EAP, 14.4 U/L (P<0.001)), and was observed to increase in parallel with well-established myocardial markers (P<0.001). Moreover, PGM activity and the lipid, thrombosis, and inflammatory biomarkers in the AMI group were higher than those in the EAP group. CONCLUSIONS: PGM activity increased with levels of myocardial, thrombosis, and inflammatory biomarkers in patients with AMI, and might be useful in diagnostic applications during the acute phase in patients with AMI.

Effect of hypothermia therapy after outpatient cardiac arrest due to ventricular fibrillation.

BACKGROUND: Several investigators have emphasized the positive effect of hypothermia therapy on patients who have suffered from cardiac arrest. Salvaging patients from circulatory collapse is a pivotal task, but it is unclear whether additional hypothermia can practically contribute to an improvement in the neurological outcome. METHODS AND RESULTS: Since December 2005, our hospital has been using hypothermia therapy. Forty-six comatose patients after recovery of spontaneous circulation were consecutively enrolled in the present study. Twenty-five of the enrolled patients received hypothermia therapy and 21 did not because they were treated prior to 2005. The time from collapse to spontaneous circulation (P=0.09), the rates of performance of bystander CPR (P=0.370) and presence of a witnessed collapse (P=0.067) were not significantly different between the recovery group (n=28) and the non-recovery group (n=18). The additional hypothermia therapy was an independent predictor of neurological recovery (P=0.005, OR 6.5, 95%CI 1.74-24.27). The recovery rate was significantly higher in patients who received hypothermia therapy (80%) compared to those who did not (38%). CONCLUSIONS: Hypothermia therapy is very useful for treating patients who have had an out-of-hospital cardiac arrest; it should be induced rapidly and smoothly.

Beta2-Adrenergic agonists suppress rat autoimmune myocarditis: potential role of beta2-adrenergic stimulants as new therapeutic agents for myocarditis.

BACKGROUND: The therapeutic potential of beta2-adrenergic receptor (AR) agonists in the treatment of autoimmune diseases has been reported. However, the role of these drugs in the myocardial structure-induced autoimmune process, which is thought to play a crucial role in the progression of myocarditis to subsequent complications, has not been elucidated. METHODS AND RESULTS: Experimental autoimmune myocarditis (EAM) was induced in rats by immunization with cardiac myosin. On daily administration from day 0 after immunization, the beta2-selective AR agonists formoterol or salbutamol ameliorated EAM on day 21 and increased myocardial interleukin-10/interferon-gamma mRNA levels. Propranolol, a nonselective beta-AR antagonist, aggravated EAM on day 21 and decreased mRNA levels, whereas metoprolol, a beta1-selective AR antagonist, showed no effect. These results were reflected in vivo by the proliferation of cardiac myosin-primed lymph node cells from drug-treated rats. In vitro addition of beta2-selective AR agonists inhibited the activation of cardiac myosin fragment-specific myocarditogenic T lymphocytes, and this effect was reversed by ICI118,551, a beta2-selective AR antagonist. Furthermore, treatment with 2 different beta2-selective AR agonists starting on day 14 also ameliorated EAM on day 21. CONCLUSIONS: beta2-AR stimulation suppressed the development of EAM by inhibiting cardiac myosin-specific T-lymphocyte activation in lymphoid organs and by shifting the imbalance in Th1/Th2 cytokine toward Th2 cytokine. Furthermore, it also ameliorated established myocardial inflammation. beta2-AR-stimulating agents may represent important immunomodulators of the cardiac myosin-induced autoimmune process and have potential as a new therapy for myocarditis.

Serum levels of interleukin-10 on admission as a prognostic predictor of human fulminant myocarditis.

OBJECTIVES: We assessed the significance of serum cytokine levels in patients with fulminant myocarditis. BACKGROUND: Although many investigations have demonstrated the crucial role of cytokines in the development of myocarditis, it remains uncertain whether serum levels of cytokines enable one to predict the prognosis of human myocarditis, especially concerning cardiogenic shock (CS) requiring a mechanical cardiopulmonary support system (MCSS). METHODS: We studied 22 consecutive patients with fulminant myocarditis and compared them with 15 patients with acute myocardial infarction (AMI) requiring MCSS. The patients with myocarditis were classified into three groups: eight patients with CS requiring MCSS on admission (group 1); six patients who unexpectedly lapsed into CS requiring MCSS more than two days after catecholamine had been initiated (group 2); and eight patients without MCSS (group 3). Furthermore, 14 patients with myocarditis requiring MCSS were divided into a fatal group (n = 5) and a survival group (n = 9). Biochemical markers, including serum cytokine levels and hemodynamic variables on admission, were analyzed. RESULTS: Serum levels of interleukin (IL)-10 and tumor necrosis factor-alpha, but not other cytokines, were significantly higher in myocarditis than in AMI. Only serum levels of IL-10 were significantly higher in group 1 and 2 than in group 3 (49.1 +/- 37.5/20.7 +/- 17.6 pg/ml vs. 2.4 +/- 1.1 pg/ml; p = 0.0008/0.0012). Serum IL-10 levels were also significantly higher in the fatal group than in the survival group with myocarditis (74.0 +/- 27.0 pg/ml vs. 16.4 +/- 8.8 pg/ml; p = 0.003). CONCLUSIONS: Serum IL-10 levels on admission enabled one to predict subsequent CS requiring MCSS and mortality of fulminant myocarditis patients.

End-tidal carbon dioxide concentration can estimate the appropriate timing for weaning off from extracorporeal membrane oxygenation for refractory circulatory failure.

Although extracorporeal membrane oxygenation (ECMO) is widely used as temporary circulation support, there are no reports of direct parameters indicating cardiac recovery to determine the timing of weaning off. Twenty-five patients supported by ECMO due to hemodynamic deterioration were divided into 2 groups according to their outcome: weaned ECMO (W: n = 18) or not (NW: n = 7). In the W group, we examined the differences in parameters between the 2 time points, ECMO introduction, and the reduction in ECMO flow to 40% of the initial setting known as the conventional recovery point (C-point). Significant differences were observed in systolic pulmonary artery pressure, the cardiac index measured by the thermodilution method, C-reactive protein, lactate, base excess, and the end-tidal CO(2) concentration (ETCO(2)). Next, by closely examining these 6 parameters measured every 12 hours, we found that only ETCO(2) had always changed steeply, like a 'flexion point' (E-point), in all W cases, but not in NW. The E-point was defined as an initial increase in ETCO(2) of >or= 5 mmHg over the preceding 12 hours with a continued rise over the next 12 hours. E-points appeared as much as 95 +/- 60 hours earlier than C-points and also preceded weaning off of ECMO. ETCO(2) can be a useful continuous parameter for predicting the adequate timing of weaning off of ECMO for circulatory failure at the bedside.

Prognostic utility of B-type natriuretic peptide assessment in stable low-risk outpatients with nonischemic cardiomyopathy after decompensated heart failure.

OBJECTIVES: We investigated the clinical utility of B-type natriuretic peptide (BNP) assay in stable outpatients with nonischemic dilated cardiomyopathy (NICM) after decompensated heart failure (HF). BACKGROUND: Patients with NICM admitted for decompensated HF frequently experience sudden death or redecompensation after hospital discharge. The prognostic value of BNP during hospitalization has been demonstrated. However, clinical utility of BNP in stable outpatient setting has been poorly investigated. METHODS: Eighty-three NICM outpatients who were clinically stable in New York Heart Association functional class 1 to 2 for 6 months after discharge for decompensated HF were enrolled, and then followed for an additional 18 months. The main end point was first readmission for decompensated HF or death. B-type natriuretic peptide levels were measured at 3-month intervals from discharge to enrollment, and echocardiographic dimensions at discharge and enrollment. RESULTS: Mean discharge BNP level was 210 +/- 148 pg/ml. Twenty-eight patients were readmitted for decompensated HF or suddenly died at a median time of 11 months from the time of discharge. Among various variables including BNP measurements, clinical parameters and echocardiographic dimensions, a 6-month post-discharge BNP of >190 pg/ml was most closely associated with combined event in the Cox proportional hazards model (hazard ratio 2.29; 95% confidence interval 1.42 to 3.56; p = 0.0005), and had the best discriminatory power (area under the receiver operating characteristic curve 0.91, sensitivity 96%; specificity 76%). CONCLUSIONS: Even in stable low-risk outpatients with NICM at 6 months after hospital discharge for decompensated HF, BNP assessment predicts a long-term risk of redecompensation.

Clinical impact of adherence to guidelines on the outcome of chronic heart failure in Japan.

The impact of guideline adherence on clinical outcomes in the management of chronic heart failure (CHF) has never been evaluated in Japan. We investigated outcomes in 92 consecutive CHF patients admitted to Kitasato University Hospital in 2004-2006 for HF exacerbation with a left ventricular ejection fraction < or = 40% by the use of class I drugs for pump-failure, as recommended in the Japanese Circulation Society guideline. Drugs, namely angiotensin-converting enzyme inhibitors (ACEI), beta-blockers (BB), spironolactone, diuretics, and cardiac glycosides were administered to 64.1%, 59.8%, 28.2%, 96.7%, and 68.0% of patients, respectively. Patients for whom adherence to the prescription of ACEI and BB as first-line agents was high had significantly and independently better prognostic outcomes for cardiac events (P = 0.0036) as well as subsequent improvements in clinical surrogate markers for HF status such as NYHA class and BNP. Addition of the 3 latter drugs to the prescription of ACEI and BB did not affect the superiority of ACE plus BB in improving the long-term prognosis. We have demonstrated that adherence to treatment guidelines for CHF is a significant predictor of subsequent cardiac events in actual practice in Japan. An effective means of improving adherence to current guideline standards of care for CHF has yet to be established.

Prognostic significance of increased serum bilirubin levels coincident with cardiac decompensation in chronic heart failure.

BACKGROUND: The aim of this study was to analyze the relationship between abnormal liver function tests (LFTs) coincident with heart failure (HF) exacerbation and subsequent long-term outcome in patients with chronic HF. METHODS AND RESULTS: The study population consisted of 183 consecutive patients admitted for HF exacerbation with left ventricular ejection fraction < or =40%. Cox proportional hazard analysis revealed that serum total bilirubin (T-Bil) levels on admission (hazard ratio 1.896, p<0.001, 95% confidence interval 1.323-2.717), but not T-Bil at discharge or other LFTs, was an independent predictor of subsequent cardiac events after hospital discharge (cardiac death or readmission for HF exacerbation) The cardiac-event-free rates significantly decreased according to increasing tertiles of T-Bil stratified by the level of 0.7 and 1.2 mg/dl (p<0.001). T-Bil on admission had significant correlations with simultaneously-measured central venous pressure (CVP) (r=0.42, p<0.01) and cardiac index (CI) (r= -0.50, p<0.01). The patients demonstrating high CVP together with low CI showed significantly increased T-Bil compared with any other group. CONCLUSIONS: Increased T-Bil coincident with cardiac decompensation predicts a worse long-term prognosis of CHF, presumably through the potential liability to both congestion and tissue hypoperfusion simultaneously when HF deteriorates.

Increased serum bilirubin levels coincident with heart failure decompensation indicate the need for intravenous inotropic agents.

We have reported that chronic heart failure (HF) patients with increased serum bilirubin coincident with acute decompensation have a poor prognosis, indicating severe congestion and low tissue perfusion. The aim of this study was to analyze the possibility of increased bilirubin coincident with acute decompensation as a parameter which indicates the need for intravenous inotropic agents. We stratified 131 decompensated chronic HF patients with a LVEF or= 1.2 mg/dL), intravenous inotropics contributed to significantly more abundant diuresis, body weight reduction, and decreases in bilirubin and serum creatinine in the first 5 in-hospital days compared to those without (group A: inotropics +; n = 24 versus group B: -; n = 38: 1726 +/- 418 versus 1458 +/- 424 mL/day: P < 0.05, -3.1 +/- 1.6 versus -2.1 +/- 2.2 kg: P < 0.05, -0.74 +/- 0.51 versus -0.04 +/- 0.60 mg/dL: P < 0.01, -0.29 +/- 0.89 versus -0.01 +/- 0.24 mg/dL: P < 0.01), in spite of no significant difference in the doses of diuretics between the 2 groups. On the contrary, patients with low bilirubin (T-Bil < 1.2 mg/dL) recovered from decompensation equally irrespective of inotropic administration (group C: inotropics +; n = 15 versus group D: -; n = 54: 1557 +/- 329 versus 1507 +/- 406 mL/day, -2.9 +/- 1.7 versus -2.8 +/- 1.5 kg, -0.01 +/- 0.25 versus -0.08 +/- 0.23 mg/dL, 0.02 +/- 0.24 versus 0.47 +/- 0.19 mg/dL; NS, respectively). Inotropics were administered after all because of unimproved hemodynamics in 26% of group B patients, compared to 4% of group D patients (P < 0.01). Increased bilirubin coincident with HF decompensation can be a useful marker indicating the need for intravenous inotropic agent administration.

Clinical characteristics of heart disease patients with a good prognosis in spite of markedly increased plasma levels of type-B natriuretic peptide (BNP): anomalous behavior of plasma BNP in hypertrophic cardiomyopathy.

BACKGROUND: Although it is not rare to encounter patients with plasma B-type natriuretic peptide (BNP) levels unequivalent to the severity of heart failure (HF), there has been little investigation to clarify the causative background of this phenomenon. METHODS AND RESULTS: Among the 1,838 outpatients whose plasma BNP was measured, persistently increased levels of BNP above 500 pg/ml was observed for more than 6 months in 14 subjects with few HF symptoms. Among these, all of 4 patients without any following cardiac events (E-/high) for 12 months showed hypertrophic nonobstructive cardiomyopathy (HNCM). When we compared the clinical parameters of these patients with those of 22 HNCM patients without any following cardiac events whose plasma BNP levels were less than 200 pg/ml, there were only 2 clinical characteristics to be distinguished: (i) plasma renin activity (PRA) and norepinephrine (NE) levels were low in spite of markedly increased levels of plasma BNP in E-/high HNCM; and (ii) echocardiographic investigation revealed that only global left atrial fractional shortening was significantly lower in E-/high HNCM. CONCLUSIONS: Plasma BNP levels do not always reflect the severity of HF in HNCM. It might be considered to utilize other clinical parameters such as NE and PRA to recognize HF severity in such patients.

Distinguishable optimal levels of plasma B-type natriuretic peptide in heart failure management based on complicated atrial fibrillation.

A B-type natriuretic peptide (BNP)-guided strategy is being widely used as a superior management technique for heart failure (HF). However, the optimal target level of BNP to improve the prognosis of HF in clinical practice remains unclear. Several studies have recently demonstrated that the existence of atrial fibrillation (AF) affects plasma BNP levels. We evaluated the prognostic value of BNP assay for HF management and found the optimal target level under the BNP-guided HF management according to the basal cardiac rhythms: AF or sinus rhythm (SR). Patients hospitalized for HF exacerbation between 1996 and 2002 were stratified into SR (n = 129) and chronic AF (CAF, n = 58) groups as basal cardiac rhythms during hospitalization. Cardiac events including death and re-admission for HF exacerbation after discharge were analyzed in relation to the plasma BNP levels at predischarge. Receiver-operating characteristic (ROC) analysis demonstrated that the cut-off values for predischarge BNP, which predict cardiac events at 36 months after discharge, were 125 pg/mL in the SR group and 165 pg/mL in the CAF group. The area under the ROC curve was 0.72 and 0.82, respectively. Stratified subgroup analysis using the Kaplan-Meier method demonstrated that the risk of a cardiac event decreased in a stepwise fashion across a decreasing predischarge BNP range above these cut-off levels, while the minimum decreased risk was recognized at a BNP range below these cut-off levels in each group. In conclusion, the optimal target levels of plasma BNP at predischarge to improve the prognosis of HF should be different and distinguishable depending on with or without AF.

Paroxysmal atrial fibrillation coincident with cardiac decompensation is a predictor of poor prognosis in chronic heart failure.

BACKGROUND: The prognostic significance of atrial fibrillation (AF) in chronic heart failure (CHF) remains poorly understood. METHODS AND RESULTS: Death and rehospitalizaion for CHF exacerbation for 427 consecutive patients hospitalized from 1996 to 2002 were retrospectively analyzed in relation to cardiac rhythm: sinus rhythm (SR; n=239) or AF (n=188). The AF group was classified according to an Intervention (n=57) or Non-Intervention (n=131) group for defibrillating AF. During the follow-up of 34+/-23 months, there was no significant difference of mortality or morbidity between the SR and AF groups, or between the Intervention and Non-Intervention groups, respectively. However, the Non-Intervention group consisted of 28 patients with paroxysmal AF (PAF), which spontaneously converted to SR during hospitalization, and 103 with chronic AF (CAF). The rehospitalization for CHF exacerbation was significantly higher in PAF than that in CAF and SR (p=0.00005 and 0.002, respectively). Multivariate Cox analysis demonstrated that, PAF, but not CAF, was a predictor of readmission (relative risk 2.30, p=0.004, 95% confidence interval 1.30 to 4.05). CONCLUSIONS: The present data implied that PAF coincident with cardiac decompensation could be a new predictor of prognosis for CHF. The management strategies of AF in CHF should be discussed according to the phenotype of AF.

Immunomodulatory effect of pentoxifylline in suppressing experimental autoimmune myocarditis.

Although a recent clinical study reported the beneficial effects of pentoxifylline (PTX), a phosphodiesterase inhibitor, on both symptoms and cardiac function in dilated cardiomyopathy (DCM), the precise mechanism of the drug has not been delineated. This study examined the efficacy of PTX in the treatment of experimental autoimmune myocarditis (EAM), as a model of the autoimmune mechanism involved in DCM. Oral PTX, or saline as control, was administered to Lewis rats at 150mg/kg body weight per day bid daily from 5 days before immunization with cardiac myosin until death on Day 21. Histological examination of the hearts showed PTX significantly reduced the severity of EAM. mRNA expression of tumor necrosis factor (TNF)-alpha, interleukin (IL)-4, IL-6, and IL-10 was significantly reduced in peripheral blood mononuclear cells, but expression of IL-4 and IL-6 was upregulated in heart tissue. PTX in vitro could suppress T cell proliferation and inhibit TNF-alpha and interferon-gamma production. In conclusion, the immunomodulatory effects of PTX had a significant therapeutic result in EAM. This is the first report to describe such an effect of PTX in a specific animal model for DCM.

Recurrent fulminant viral myocarditis with a short clinical course.

A 75-year-old man recovered from an episode of acute influenza. A myocarditis with a normalized level of serum cardiac troponin T, but less than 2 weeks after recovery, he rapidly fell into cardiogenic shock and died of fulminant myocarditis. The autopsied heart showed marked inflammatory cell infiltration that mainly consisted of mononuclear cells positive for CD8, suggesting that the second bout of myocarditis was caused by viral re-infection.