Existence of reservoir with finite-dimensional output for universal reservoir computing.

In this paper, we prove the existence of a reservoir that has a finite-dimensional output and makes the reservoir computing model universal. Reservoir computing is a method for dynamical system approximation that trains the static part of a model but fixes the dynamical part called the reservoir. Hence, reservoir computing has the advantage of training models with a low computational cost. Moreover, fixed reservoirs can be implemented as physical systems. Such reservoirs have attracted attention in terms of computation speed and energy consumption. The universality of a reservoir computing model is its ability to approximate an arbitrary system with arbitrary accuracy. Two sufficient reservoir conditions to make the model universal have been proposed. The first is the combination of fading memory and the separation property. The second is the neighborhood separation property, which we proposed recently. To date, it has been unknown whether a reservoir with a finite-dimensional output can satisfy these conditions. In this study, we prove that no reservoir with a finite-dimensional output satisfies the former condition. By contrast, we propose a single output reservoir that satisfies the latter condition. This implies that, for any dimension, a reservoir making the model universal exists with the output of that specified dimension. These results clarify the practical importance of our proposed conditions.

Automatic Temperature Parameter Tuning for Reinforcement Learning Using Path Integral Policy Improvement.

In this article, we propose a novel variant of path integral policy improvement with covariance matrix adaptation ( [Formula: see text] - [Formula: see text] ), which is a reinforcement learning (RL) algorithm that aims to optimize a parameterized policy for the continuous behavior of robots. [Formula: see text] - [Formula: see text] has a hyperparameter called the temperature parameter, and its value is critical for performance; however, little research has been conducted on it and the existing method still contains a tunable parameter, which can be critical to performance. Therefore, tuning by trial and error is necessary in the existing method. Moreover, we show that there is a problem setting that cannot be learned by the existing method. The proposed method solves both problems by automatically adjusting the temperature parameter for each update. We confirmed the effectiveness of the proposed method using numerical tests.

Nonessentiality of Reservoir's Fading Memory for Universality of Reservoir Computing.

This article describes a novel sufficient condition concerning approximations with reservoir computing (RC). Recently, RC using a physical system as the reservoir has attracted attention. Because many physical systems are modeled as state-space systems, it is necessary to guarantee the approximations given by reservoirs represented as nonlinear state-space systems. There are two problems with existing approaches: a reservoir must have a property called fading memory and must be represented as a set of maps between input and output signals on the bi-infinite-time (BIT) interval. These two conditions are too strict for reservoirs represented as nonlinear state-space systems as they require the reservoir to have a unique equilibrium state for the zero input. This article proposes an approach that employs operators from right-infinite-time (RIT) inputs to RIT outputs. Furthermore, we develop a novel extension of the Stone-Weierstrass theorem to handle discontinuous functions. To apply the extended theorem, we define functionals corresponding to operators and introduce a metric on the domain of the functionals. The resulting sufficient condition does not require the reservoir to have fading memory or continuity with respect to inputs and time. Therefore, our result guarantees the approximations with very common reservoirs and provides a rationale for physical RC. We present an example of a physical reservoir without fading memory. With the example reservoir, the RC model successfully approximates NARMA10, a benchmark task for time series predictions.

Primary results from the Japanese Heart Failure and Sudden Cardiac Death Prevention Trial (HINODE).

AIMS: The HINODE study aimed to analyse rates of mortality, appropriately treated ventricular arrhythmias (VA), and heart failure in Japanese patients and compared with those in Western patients. METHODS AND RESULTS: After treatment decisions following contemporary practice in Japan, patients were prospectively enrolled into four cohorts: (i) internal cardioverter-defibrillator (ICD), (ii) cardiac resynchronization therapy (CRT) defibrillator (CRT-D), (iii) standard medical therapy ('non-device': ND), or (iv) pacing (indicated for CRT; received pacemaker or CRT pacing). Cohorts 1-3 required a left ventricular ejection fraction ≤35%, a history of heart failure, and a need for primary prevention of sudden cardiac death based on two to five previously identified risk factors. Endpoint outcomes were adjudicated by the independent committees. ICD and CRT-D cohorts, considered as high-voltage (HV) cohorts, were pooled for Kaplan-Meier analysis and propensity-matched to Multicenter Automatic Defibrillator Implantation Trial-Reduce Inappropriate Therapy (MADIT-RIT) arm B and C patients. The study enrolled 354 patients followed for 19.6 ± 6.5 months, with a minimum of 12 months. Propensity-matched HV cohorts showed comparable VA (P = 0.61) and mortality rates (P = 0.29) for HINODE and MADIT-RIT. The ND cohort presented a high crossover rate to ICD therapy (6.1%, n = 7/115), and the CRT-D cohort showed elevated mortality rates. The pacing cohort revealed that patients implanted with pacemakers had higher mortality (26.0%) than those with CRT-Pacing (8.4%, P = 0.05). CONCLUSIONS: The mortality and VA event rates of landmark trials are applicable to patients with primary prevention in Japan. Patients who did not receive guideline-indicated CRT devices had poor outcomes.

Clinical value of the HATCH score for predicting adverse outcomes in patients with heart failure.

The HATCH score is employed as a risk assessment tool for atrial fibrillation (AF) development. However, the impact of the HATCH score on the long-term adverse outcomes in patients with acute heart failure (AHF) remains unknown. We investigated the clinical value of the HATCH score in patients with AHF. From a multicenter AHF registry, we retrospectively evaluated 1543 consecutive patients who required hospitalization owing to AHF (median age, 78 [69-85] years; 42.3% women) from January 2012 to December 2019. These patients were divided into five risk groups based on their HATCH score at admission (scores 0, 1, 2, 3, and 4-7). The correlation between the HATCH score and the composite outcome, including all-cause mortality and re-hospitalization due to HF, was analyzed using Kaplan-Meier and Cox proportional-hazard analyses. The median HATCH score was 2 [1-3], and the median age was 78 years (69-85 years). During the follow-up period (median, 16.8 months), the composite endpoint occurred in 691 patients (44.8%), including 416 (27%) patients who died (with 65 [4.2%] in-hospitalization deaths) and 455 (29.5%) patients requiring re-hospitalizations due to HF. The Kaplan-Meier analysis showed a significant increase in the composite endpoint with an increasing HATCH score (log-rank, p < 0.001). The multivariate Cox regression model revealed that the HATCH score was an independent predictor of the composite endpoint (hazard ratio [HR] 1.181; 95% confidence interval [CI]: 1.111-1.255; p < 0.001) with all-cause mortality (HR 1.153, 95% CI 1.065-1.249; p < 0.001) and re-hospitalizations due to HF (HR 1.21; 95% CI 1.124-1.303; p < 0.001) in patients with AHF, regardless of the presence or absence of AF, ejection fraction, and etiology. The HATCH score is an independent predictor of adverse outcomes in patients with AHF.

Clinical Impact of Worsening Renal Function in Elderly Patients with Acute Decompensated Heart Failure.

Background and Objectives: The clinical significance of worsening renal function (WRF) in elderly patients with acute decompensated heart failure (ADHF) is not completely understood. We compared the clinical conditions between younger and elderly patients with ADHF after the appearance of WRF to establish its prognostic influence. Methods: We included 654 consecutive patients (37% women) admitted for ADHF. We divided the patients into four groups according to their age (<80 years, under-80, n=331; ≥80 years, over-80, n=323) and to their WRF statuses (either WRF or non-WRF group). We defined WRF as an increase in serum creatinine level ≥0.3 mg/dL or ≥150% within 48 hours after hospital arrival (under-80, n=62; over-80, n=75). The primary endpoint was a composite of cardiac events within 1 year. Results: The survival analyses revealed that the WRF group had significantly more cardiac events than the non-WRF group in patients in the over-80 group (log-rank p=0.025), but not in those of the under-80 group (log-rank p=0.50). The patients in the over-80, WRF group presented more significant mean blood pressure (MBP) drops than those in the over-80 non-WRF group (p=0.003). Logistic regression analyses revealed that higher MBP at admission was a significant predictor of WRF. Conclusions: WRF is a predictor of poor outcomes in elderly patients with ADHF.

Remote Management of Pacemaker Patients With Biennial In-Clinic Evaluation: Continuous Home Monitoring in the Japanese At-Home Study: A Randomized Clinical Trial.

BACKGROUND: Current expert consensus recommends remote monitoring for cardiac implantable electronic devices, with at least annual in-office follow-up. We studied safety and resource consumption of exclusive remote follow-up (RFU) in pacemaker patients for 2 years. METHODS: In Japan, consecutive pacemaker patients committed to remote monitoring were randomized to either RFU or conventional in-office follow-up (conventional follow-up) at twice yearly intervals. RFU patients were only seen if indicated by remote monitoring. All returned to hospital after 2 years. The primary end point was a composite of death, stroke, or cardiovascular events requiring surgery, and the primary hypothesis was noninferiority with 5% margin. RESULTS: Of 1274 randomized patients (50.4% female, age 77±10 years), 558 (RFU) and 550 (Conventional follow-up) patients reached either the primary end point or 24 months follow-up. The primary end point occurred in 10.9% and 11.8%, respectively (P=0.0012 for noninferiority). The median (interquartile range) number of in-office follow-ups was 0.50 (0.50-0.63) in RFU and 2.01 (1.93-2.05) in conventional follow-up per patient-year (P<0.001). Insurance claims for follow-ups and directly related diagnostic procedures were 18 800 Yen (16 500-20 700 Yen) in RFU and 21 400 Yen (16 700-25 900 Yen) in conventional follow-up (P<0.001). Only 1.4% of remote follow-ups triggered an unscheduled in-office follow-up, and only 1.5% of scheduled in-office follow-ups were considered actionable. CONCLUSIONS: Replacing periodic in-office follow-ups with remote follow-ups for 2 years in pacemaker patients committed to remote monitoring does not increase the occurrence of major cardiovascular events and reduces resource consumption. Registration: URL: https://clinicaltrials.gov; Unique identifier: NCT01523704.

Digital zoom is a useful, simple, and cost-effective method of reducing radiation exposure in percutaneous coronary intervention.

Reducing radiation exposure is a very important issue in interventional cardiology techniques such as percutaneous coronary intervention. Although novel techniques to reduce radiation exposure are valuable, we should also reconsider older techniques. Digital zoom has been available in Japan from 2005. Digital zoom enlarges an 8-inch field of view (FOV) by 1.2 times, allowing visualization of a 6.7-inch FOV without FOV switching. We identified 2101 suitable cases of percutaneous intervention (PCI) and divided them into two groups according to the use of digital zoom; 1195 patients were included in the digital zoom group and 906 patients in the conventional group. We collected data regarding the reference air kerma (RAK) and dose-area product (DAP). We calculated RAK and DAP per minute fluoroscope time (RAK/min, DAP/min, respectively). There were intergroup differences in RAK, DAP, RAK/min, and DAP/min (digital zoom group vs conventional group; RAK, 1590 mGy [990-2410] vs 1850 [1220-2720], p < 0.01, RAK/min; 54.7 mGy/min [38.5-73.2] vs 71.2 [51.5-93.0], p < 0.01; DAP, 16,000 cGy × cm2 [10,300-24,400] vs 20,700 [13,400-29,500], p < 0.001; DAP/min, 557 cGy × cm2/min [392-737] vs 782 [571-1010], p < 0.01, respectively). Because of baseline differences between the two groups, we performed propensity score matching. Even after score matching, there were intergroup differences in DAP, DAP/min, RAK, and RAK/min. Furthermore, the least squares method showed that digital zoom is a significant predictor of RAK (ß = 0.14, p < 0.01) and DAP (ß = 0.20, p < 0.01). Digital zoom is an older cost-effective technique that can significantly reduce radiation exposure in PCI.

Correction to: The lactate clearance calculated using serum lactate level 6 h after is an important prognostic predictor after extracorporeal cardiopulmonary resuscitation: a single-center retrospective observational study.

[This corrects the article DOI: 10.1186/s40560-018-0302-z.].

A Decision Tree-Based Survival Analysis of Patients with a History of Inappropriate Implantable Cardioverter-Defibrillator Therapy.

Implantable cardioverter-defibrillators (ICDs) improve survival in patients who are at risk of sudden death. However, inappropriate therapy is commonly given to ICD recipients, and this situation may be associated with an increased risk of death. This study aimed to construct a risk stratification scheme by using decision tree analysis in patients who received inappropriate ICD therapy.Mortality was calculated from a retrospective data analysis of a multicenter cohort involving 417 ICD recipients. Inappropriate therapy was defined as therapy for nonventricular arrhythmias, including sinus tachycardia, supraventricular tachycardia, atrial fibrillation/flutter, oversensing, and lead failure. Inappropriate therapy included antitachycardia pacing, cardioversion, and defibrillation. The prognostic factors were identified by a Cox proportional hazards regression analysis, and we constructed a decision tree.During an average follow-up of 5.2 years, 48 patients (12%) had all-cause death. A multivariate Cox hazard model revealed that the age (hazard ratio [HR] 1.06, P < 0.001), ln B-type natriuretic peptide (BNP) (HR 1.47, P = 0.02), nonsinus rhythm at implantation (HR 2.70, P < 0.05), and inappropriate therapy occurring during sedentary/awake conditions (HR 3.51, P = 0.001) correlated with an increased risk of mortality. An inappropriate therapy due to abnormal sensing (HR 0.16, P = 0.04) decreased the risk of mortality. Furthermore, a decision tree analysis stratified the patients well by using 4 covariates: BNP, activity at the time of inappropriate therapy, mechanism of inappropriate therapy, and baseline rhythm at ICD implantation (log-rank test, P < 0.0001).We identified the predictors of mortality in inappropriate ICD therapy recipients and constructed a risk stratification scheme by using decision tree analysis.

The lactate clearance calculated using serum lactate level 6 h after is an important prognostic predictor after extracorporeal cardiopulmonary resuscitation: a single-center retrospective observational study.

BACKGROUND: Serum lactate level can predict clinical outcomes in some critical cases. In the clinical setting, we noted that patients undergoing extracorporeal cardiopulmonary resuscitation (ECPR) and with poor serum lactate improvement often do not recover from cardiopulmonary arrest. Therefore, we investigated the association between lactate clearance and in-hospital mortality in cardiac arrest patients undergoing ECPR. METHODS: Serum lactate levels were measured on admission and every hour after starting ECPR. Lactate clearance [(lactate at first measurement - lactate 6 h after)/lactate at first measurement × 100] was calculated 6 h after first serum lactate measurement. All patients who underwent ECPR were registered retrospectively using opt-out in our outpatient's segment. RESULT: In this retrospective study, 64 cases were evaluated, and they were classified into two groups according to lactate clearance: high-clearance group, > 65%; low-clearance group, ≤ 65%. Surviving discharge rate of high-clearance group (12 cases, 63%) is significantly higher than that of low-clearance group (11 cases, 24%) (p < 0.01). Considering other confounders, lactate clearance was an independent predictor for in-hospital mortality (odds ratio, 7.10; 95% confidence interval, 1.71-29.5; p < 0.01). Both net reclassification improvement (0.64, p < 0.01) and integrated reclassification improvement (0.12, p < 0.01) show that adding lactate clearance on established risk factors improved the predictability of in-hospital mortality. CONCLUSION: In our study, lactate clearance calculated through arterial blood gas analysis 6 h after ECPR was one of the most important predictors of in-hospital mortality in patients treated with ECPR after cardiac arrest.

Inappropriate implantable cardioverter defibrillator shocks-incidence, effect, and implications for driver licensing.

PURPOSE: Patients with implantable cardioverter defibrillators (ICDs) have an ongoing risk of sudden incapacitation that may cause traffic accidents. However, there are limited data on the magnitude of this risk after inappropriate ICD therapies. We studied the rate of syncope associated with inappropriate ICD therapies to provide a scientific basis for formulating driving restrictions. METHODS: Inappropriate ICD therapy event data between 1997 and 2014 from 50 Japanese institutions were analyzed retrospectively. The annual risk of harm (RH) to others posed by a driver with an ICD was calculated for private driving habits. We used a commonly employed annual RH to others of 5 in 100,000 (0.005%) as an acceptable risk threshold. RESULTS: Of the 4089 patients, 772 inappropriate ICD therapies occurred in 417 patients (age 61 ± 15 years, 74% male, and 65% secondary prevention). Patients experiencing inappropriate therapies had a mean number of 1.8 ± 1.5 therapy episodes during a median follow-up period of 3.9 years. No significant differences were found in the age, sex, or number of inappropriate therapies between patients receiving ICDs for primary or secondary prevention. Only three patients (0.7%) experienced syncope associated with inappropriate therapies. The maximum annual RH to others after the first therapy in primary and secondary prevention patients was calculated to be 0.11 in 100,000 and 0.12 in 100,000, respectively. CONCLUSIONS: We found that the annual RH from driving was far below the commonly cited acceptable risk threshold. Our data provide useful information to supplement current recommendations on driving restrictions in ICD patients with private driving habits.

Quantitative assessment of arterial stiffness by multiphase analysis in retrospectively electrocardiogram-gated multidetector row computed tomography: comparison between patients under chronic hemodialysis and age-matched controls.

PURPOSE: To determine the feasibility of assessment of arterial stiffness with multiphase analysis of data sets of retrospectively electrocardiogram (ECG)-gated multidetector row computed tomography (MDCT) coronary angiography by comparing wall stiffness of the descending aorta between patients under chronic hemodialysis and age-matched controls undergoing imaging for by-pass graft. MATERIALS AND METHODS: We retrospectively assessed 33 patients composed of 10 hemodialysis patients and 23 age-matched control subjects, who underwent MDCT to evaluate the coronary arterial lesions and pulse wave velocity (PWV) measurement. Scan data were reconstructed at 25 phases between 0% and 96% of the R-R intervals with an increment of 4%. Pixel-based measurements of arterial dimensions were performed at 1 cross-section of the descending aorta in a transaxial plane including the aortic valve at its widest. Aortic distensibility (AD) was calculated as follows: AD = (maximal dimension -- minimal dimension)/minimal dimension x pulse pressure. Comparison in the AD was performed between the hemodialysis patients and control subjects. Correlation between the AD and PWV were assessed separately in the patients under hemodialysis and age-matched controls. RESULTS: AD was significantly smaller in patients under hemodialysis than in age-matched controls. The square of PWV correlated better with the inverse of the AD in the control subjects compared to patients on hemodialysis. CONCLUSION: Multiphase analysis in ECG-gated MDCT enables us to assess stiffness of the descending aorta objectively and noninvasively.

Pressure overload-induced cardiomyopathy in heterozygous carrier mice of carnitine transporter gene mutation.

Primary systemic carnitine deficiency is an autosomal recessive disorder caused by a decreased renal reabsorption of carnitine because of mutations of the carnitine transporter OCTN2 gene, and hypertrophic cardiomyopathy is a common clinical feature of homozygotes. Although heterozygotes for OCTN2 mutations are generally healthy with normal cardiac performance, heterozygotes may be at risk for cardiomyopathy in the presence of additional risk factors, such as hypertension. To test this hypothesis, we investigated the effects of surgically induced pressure overload on the hearts of heterozygous mutants of a murine model of OCTN2 mutation, juvenile visceral steatosis mouse (jvs/+). Eleven-week-old jvs/+ mice and age-matched wild-type mice were used. At baseline, there were no differences in physical characteristics between wild-type and jvs/+ mice. However, plasma and myocardial total carnitine levels in jvs/+ mice were lower than in wild-type mice. Both wild-type and jvs/+ mice were subjected to ascending aortic constriction with or without 1% l-carnitine supplementation for 4 weeks. At 4 weeks after ascending aortic constriction, jvs/+ mice showed an exaggeration of cardiac hypertrophy and pulmonary congestion, further increased gene expression of atrial natriuretic peptide in the left ventricles, further deterioration of left ventricular fractional shortening, reduced myocardial phosphocreatine:adenosine triphosphate ratio, and increased mortality compared with wild-type mice; l-carnitine supplementation prevented these changes in jvs/+ mice subjected to ascending aortic constriction. In conclusion, cardiomyopathy and heart failure with energy depletion may be induced by pressure overload in heterozygotes for OCTN2 mutations and could be prevented by l-carnitine supplementation.

[Promising efficacy of the sirolimus-eluting stent in patients with acute myocardial infarction].

OBJECTIVES: This study investigated the safety and efficacy of sirolimus-eluting stents (SESs) on early and late outcomes in patients with acute myocardial infarction. METHODS: A series of 100 consecutive patients (September 2004 to November 2005)with acute myocardial infarction undergoing primary stenting using SES ptember 24 hr) was compared with 100 consecutive patients (September 2003 to August 2004) treated with bare metal stent (BMS). The frequency of major adverse cardiac events (MACE) and stent thrombosis, and status of ticlopidine administration were assessed at 270 days. RESULTS: The rates of premature discontinuation of ticlopidine (SES group <3 months: 11%, BMS group <1 month: 11%, p = NS) and stent thrombosis (SES group: 1%, BMS group: 0%, p = NS) were similar in the two groups. At follow-up, restenosis rate and target vessel revascularization rate were lower in the SES group(4% vs 19%, p < 0.001 and 4% vs 10%, p = 0.149, respectively). Furthermore, the occurrence of MACE at 270 days was significantly less frequent in the SES group compared with the BMS group (6% vs. 17%, p = 0.038). Multivariate analysis showed SES use tended to predict 270-day MACE (hazard ratio 0.37, 95% confidence interval 0.14-1.02, p = 0.055). Culprit lesion located in the left main trunk was identified as an independent predictor of 270-day MACE (hazard ratio 5.43, 95% confidence interval 1.07-27.59, p = 0.041). CONCLUSIONS: The use of a SES was not associated with increased risk of stent thrombosis compared with a BMS. With lower rates of restenosis and subsequent target vessel revascularization, SES placement could provide superior outcomes in patients with acute myocardial infarction.

Upregulation of renal eNOS by high-sodium diet facilitates hypertension in doxorubicin-treated rats through enhanced oxidative stress.

It is known that renal nitric oxide (NO) is an important controller of urinary sodium excretion. A defect in the kidney's NO system could cause salt-sensitive hypertension. Since it has been demonstrated that doxorubicin binds to the reductase domain of endothelial NO synthase (eNOS) and generates superoxide in vitro, we tested our hypothesis that a high-sodium diet would upregulate the expression of eNOS and enhance oxidative stress in the kidney of doxorubicin-treated rats, resulting in a facilitation of hypertension. At 4 weeks after treatment with doxorubicin in Sprague-Dawley rats, the systolic blood pressure significantly increased only in the high-sodium diet group. The expressions of eNOS protein in the renal cortex and medulla were significantly higher in high-sodium groups than in normal-sodium groups, regardless of doxorubicin treatment. In rats treated with doxorubicin, a biomarker of oxidative damage 8-hydroxy-2'-deoxyguanosine (8-OHdG) immunohistological staining of renal tissues showed strong staining of the proximal and distal tubules. In particular, rats with doxorubicin in the high-sodium diet group demonstrated a significant increase in urinary exertion of 8-OHdG as well as more prominently stained tubules against 8-OHdG antibody, but markedly lower urinary NO(x) excretion than in rats without doxorubicin, even than in the untreated, low-sodium group. In conclusion, these results indicate that the oxidative stress induced by doxorubicin impairs NO production in the kidney. As such, doxorubicin treatment appears to contribute to the development of salt-sensitive hypertension through reductive activation of upregulated eNOS by a high-sodium diet instead of NO production.

Combined therapy with PPARalpha agonist and L-carnitine rescues lipotoxic cardiomyopathy due to systemic carnitine deficiency.

OBJECTIVE: Peroxisome proliferator-activated receptors (PPAR) are ligand-activated transcription factors that belong to the nuclear hormone receptor superfamily and are key regulators of fatty acid oxidation (FAO) in the heart. Systemic carnitine deficiency (SCD) causes disorders of FAO and induces hypertrophic cardiomyopathy with lipid accumulation. We hypothesized that activation of PPARalpha by fenofibrate, a PPARalpha agonist, in addition to conventional L-carnitine supplementation may exert beneficial effects on the lipotoxic cardiomyopathy in juvenile visceral steatosis (JVS) mouse, a murine model of SCD. METHODS: Both wild-type (WT) and JVS mice were fed a normal chow, 0.2% fenofibrate containing chow (FE), a 0.1% L-carnitine containing chow (CA) or a 0.1% L-carnitine + 0.2% fenofibrate containing chow (CA + FE) from 4 weeks of age. Four to 8 animals per group were used for each experiment and 9 to 11 animals per group were used for survival analysis. RESULTS: At 8 weeks of age, JVS mice exhibited marked ventricular hypertrophy, which was more attenuated by CA + FE than by CA or FE alone. CA + FE markedly reduced the high plasma and myocardial triglyceride levels and increased the low myocardial ATP content to control levels in JVS mice. In JVS mice, myocardial 1,2-diacylglycerol (DAG) was significantly increased and showed a distinct fatty acid composition with elevation of 18:1(n-7,9) and 18:2(n-6) fatty acids compared with that in WT mice. CA + FE significantly altered the fatty acid composition of DAG and inhibited the membrane translocation of cardiac protein kinase C beta2 in JVS mice. Furthermore, CA + FE prevented the progressive left ventricular dysfunction and dramatically improved the survival rate in JVS mice (survival rate at 400 days after birth: 89 vs. 0%, P < 0.0001). CONCLUSIONS: PPARalpha activation, in addition to l-carnitine supplementation, may rescue the detrimental lipotoxic cardiomyopathy in SCD by improving cardiac energy and lipid metabolism as well as systemic lipid metabolism.

Fenofibrate activates AMPK and increases eNOS phosphorylation in HUVEC.

Fenofibrate improves endothelial function by lipid-lowering and anti-inflammatory effects. Additionally, fenofibrate has been demonstrated to upregulate endothelial nitric oxide synthase (eNOS). AMP-activated protein kinase (AMPK) has been reported to phosphorylate eNOS at Ser-1177 and stimulate vascular endothelium-derived nitric oxide (NO) production. We report here that fenofibrate activates AMPK and increases eNOS phosphorylation and NO production in human umbilical vein endothelial cells (HUVEC). Incubation of HUVEC with fenofibrate increased the phosphorylation of AMPK and acetyl-CoA carboxylase. Fenofibrate simultaneously increased eNOS phosphorylation and NO production. Inhibitors of protein kinase A and phosphatidylinositol 3-kinase failed to suppress the fenofibrate-induced eNOS phosphorylation. Neither bezafibrate nor WY-14643 activated AMPK in HUVEC. Furthermore, fenofibrate activated AMPK without requiring any transcriptional activities. These results indicate that fenofibrate stimulates eNOS phosphorylation and NO production through AMPK activation, which is suggested to be a novel characteristic of this agonist and unrelated to its effects on peroxisome proliferator-activated receptor alpha.

Inverse correlation between soluble CD40 ligand and soluble CD40 is absent in patients with unstable angina.

The CD40/CD40 ligand (CD40L) system mediates inflammatory processes important in atherogenesis and plaque instability. The expression of CD40L on activated T cells was suppressed by soluble CD40 (sCD40) in vitro. However, the relationship between soluble CD40L (sCD40L) and sCD40 in unstable angina (UA) is still unknown. Thirty-seven consecutive patients with recent chest pain or discomfort were recruited. Patients with both Braunwald's class IB-IIIB and with coronary stenosis (or stenoses) of >75% were assigned to the UA group (n = 19, aged 67.2 +/- 8.2 years), and the rest to the control group (n = 18, aged 63.4 +/- 8.7 years). The serum levels of sCD40L and sCD40, and the plasma levels of matrix metalloproteinase (MMP)-9, were measured by enzyme-linked immunosorbent assays. A significantly inverse correlation between sCD40L and sCD40 was shown in the controls (r = -0.72, P = 0.0007), but was absent in the UA group (r = -0.16, P not significant), although there was no statistical significance between these groups in terms of serum levels of sCD40L or sCD40. The difference of the regression slopes of these regression lines was statistically significant (P < 0.01). Additionally, there was a significant correlation between sCD40 and plasma levels of MMP-9 in the patients with and without UA (r = 0.58, P = 0.0096), but no significant correlation between sCD40L and MMP-9 levels (r = 0.00, P not significant). The balance between CD40 and CD40L may be lost in patients with UA. Soluble CD40 expression may also be related to MMP-9 expression in atherosclerotic tissues.

Dietary fish oil attenuates cardiac hypertrophy in lipotoxic cardiomyopathy due to systemic carnitine deficiency.

OBJECTIVE: 1,2-Diacylglycerol (DAG), a lipid second messenger that activates protein kinase C (PKC), is increased with a distinct fatty acid composition in the heart of the juvenile visceral steatosis (JVS) mouse, which develops pathological cardiac hypertrophy with lipid accumulation induced by the perturbation of fatty acid beta-oxidation due to systemic carnitine deficiency. Fish oil (FO) may exert its beneficial effects on the cardiomyopathy in JVS mice by modifying the molecular species composition of myocardial DAG. To test this hypothesis, we investigated the effects of dietary FO on the hypertrophied hearts in JVS mice. METHODS: Both control and JVS mice were fed a FO diet (containing 10% FO) or a standard diet from 4 weeks of age. RESULTS: At 8 weeks of age, the ventricular-to-body weight ratio in JVS mice was 2.7-fold higher than that in controls (9.9 +/- 0.1 vs. 3.7 +/- 0.1 mg/g, P < 0.01) and was reduced by dietary FO (7.7 +/- 0.1 mg/g, P < 0.01 vs. JVS mice). In JVS mice, myocardial DAG levels were elevated by 2.3-fold with a distinct fatty acid composition with increases in C18:1n-7,9 and C18:2n-6 fatty acids compared with controls; dietary FO had no effects on the total DAG levels but significantly altered the fatty acid composition of DAG with reduction of both fatty acid species. Immunoblot analysis showed that dietary FO prevented the membrane translocation of cardiac PKCs alpha, beta2, and epsilon in JVS mice. Dietary FO did not affect the plasma and myocardial total carnitine levels in JVS mice. Furthermore, dietary FO significantly improved the progressive left ventricular dysfunction and survival rate in JVS mice. CONCLUSIONS: Dietary FO may attenuate cardiac hypertrophy with improvements in cardiac function and survival in JVS mice via modification of the molecular species composition of myocardial DAG and the consequent inhibition of PKC redistribution. These results suggest the implication of the molecular species composition of DAG in the pathogenesis of lipotoxic cardiomyopathy due to perturbations of fatty acid beta-oxidation.