Role of diacylglycerol kinase in cellular regulatory processes: a new regulator for cardiomyocyte hypertrophy

Diacylglycerol (DAG) kinase (DGK) phosphorylates and converts DAG to phosphatidic acid. DGK regulates cellular DAG levels and attenuates DAG signaling. The 10 mammalian DGK isoforms have been identified to date. In cardiac myocytes, DGKalpha, epsilon, and zeta are expressed, and DGKzeta is the predominant isoform. DGKzeta inhibits protein kinase C (PKC) activation and subsequent hypertrophic programs in response to endothelin-1 (ET-1) in neonatal rat cardiomyocytes. DGKzeta blocks cardiac hypertrophy induced by G protein-coupled receptor agonists and pressure overload in vivo. DGKzeta attenuates ventricular remodeling and improves survival after myocardial infarction. These data provide a novel insight for subcellular mechanisms of cardiac hypertrophy and heart failure, and DGKzeta may be a new therapeutic target to prevent cardiac hypertrophy and progression to heart failure.     

Decreased calcitonin gene-related peptide expression in the dorsal root ganglia of TNF-deficient mice in a monoiodoacetate-induced knee osteoarthritis model

Background: The detailed mechanisms of knee osteoarthritis (OA) pain have not been clarified, but involvement of inflammatory cytokines such as tumor necrosis factor-alpha (TNF) has been suggested. The present study aimed to investigate the more detailed neurological involvement of TNF in joint pain using a TNF-knockout mouse OA model. Methods: The right knees of twelve-week-old C57BL/6J wild and TNF-deficient knockout (TNF-ko) mice (n=15, each group) were given a single intra-articular injection of 10 µg monoiodoacetate in 10 mL sterile saline. The left knees were only punctured as the control. Evaluations were performed immediately after the injection (baseline) and at 7, 14, and 28 days after the injection with a subsequent intra-articular injection of neurotracer into both knees. The animals were evaluated for immunofluorescence of the lumbar dorsal root ganglia (DRG) innervating the knee joints. The injected knees were observed macroscopically and mouse pain-related behaviors were scored. Results: Macroscopic observation showed similar knee OA development in both wild and TNF-ko mice. Calcitonin gene-related peptide (CGRP, a neuropeptide identified as a inflammatory pain-related biomarker) was significantly increased in DRG neurons innervating OA-induced knee joints with significantly less CGRP expression in TNF-ko animals. Pain-related behavior scoring showed a significant increase in pain in OA-induced joints, but there was no significant difference in pain observed between the wild and TNF-ko mice. Conclusions: The result of the present study indicates the possible association of TNF-alpha in OA pain but not OA development.     

Elevated serum fibrin-monomer levels are associated with high long-term cerebrovascular event rates in acute ischemic stroke patients.

BACKGROUND: Serum fibrin-monomer (FM) is a precursor of stable fibrin, and is a sensitive marker of a systemic hypercoagulable state. It has been reported that, in patients with acute ischemic stroke, higher levels of serum FM reflect intracardiac thrombus formation. METHODS AND RESULTS: Serum coagulation and fibrinolytic activity were measured in 113 patients with acute ischemic stroke within 7 (6+/-1) days after onset. The patients were followed for a mean of 354 (range 36-585) days. The primary endpoints were ischemic stroke recurrence with/without death. FM was markedly higher in the 19 cases with stroke recurrence (49.6+/-53.6 microg/ml) than in the 94 patients without stroke recurrence (14.6+/-30.5 microg/ml; p=0.008). The cerebrovascular event rates were markedly higher in the 12 cases with FM > or =16.5 microg/ml (37.5%) than in the 7 cases with FM <16.5 microg/ml (8.6%; p<0.001). Cox proportional hazards multivariate analysis showed that the FM level was an independent predictor of ischemic stroke recurrence with/without death (hazard ratio, 1.516 per + 1 standard deviation increase; 95% confidence interval, 1.042-2.180; p=0.036). CONCLUSIONS: Elevated serum FM levels in hospitalized ischemic stroke patients may be associated with a persistent systemic hypercoagulable state and high long-term rates of cerebrovascular events.     

Significance of transient left ventricular wall thickening in acute lymphocytic myocarditis

Transient left ventricular (LV) wall thickening is observed in patients with acute lymphocytic myocarditis. The present study was undertaken to clarify the significance of transient LV wall thickening in patients with this disease. The subjects comprised 25 patients with acute lymphocytic myocarditis. Echocardiography was used to measure the thickness of the interventricular septum (IVS) and the LV posterior wall (PW) at four time points after myocarditis onset – namely, on days 1–3, 6–8, 13–15, and 28–30 – to clarify the timing and frequency of wall thickening. The 25 patients were divided into a fulminant myocarditis group (n = 14) and a nonfulminant myocarditis group (n = 11), and the relationship between LV wall thickening and myocarditis severity was investigated. Left ventricular wall thickening was greatest on days 1–3 after myocarditis onset (IVS: 13.3 ± 3.2 mm; PW: 12.1 ± 2.6 mm), with this finding being noted in 14 of the 25 cases (56%). By days 6–8, the thickness of IVS had virtually normalized to 10.6 ± 1.6 mm (P < 0.0001) and that of PW to 10.2 ± 1.4 mm (P = 0.0006). The thickness of the IVS and PW on days 1–3 after myocarditis onset were 14.6 ± 3.7 and 13.0 ± 2.9 mm, respectively, in the fulminant group (P = 0.014), and 11.5 ± 0.9 and 10.9 ± 1.4 mm, respectively, in the nonfulminant group (P = 0.039). In lymphocytic myocarditis, LV wall thickening is greatest on days 1–3 after myocarditis onset and improves to near normal by days 6–8. Such transient LV wall thickening occurs in approximately 50% of cases. Left ventricular wall thickening was more marked in the fulminant compared with the nonfulminant group.     

Low T3 Syndrome Is Associated With High Mortality in Hospitalized Patients With Heart Failure

Background

We aimed to clarify the prognosis and pathophysiological parameters of low T3 syndrome in patients with heart failure (HF).

Subclinical Hypothyroidism Is Associated With Adverse Prognosis in Heart Failure Patients

Background

It is widely recognized that overt hyper- as well as hypothyroidism are potential causes of heart failure (HF). Additionally it has been recently reported that subclinical hypothyroidism (sub-hypo) is associated with atherosclerosis, development of HF, and cardiovascular death. We aimed to clarify the effect of sub-hypo on prognosis of HF, and underlying hemodynamics and exercise capacity.

Hemodialysis improves myocardial interstitial edema and left ventricular diastolic function in patients with end-stage renal disease: noninvasive assessment by ultrasonic tissue characterization

Congestive heart failure is the most common cause of mortality in patients with end-stage renal disease (ESRD). Ultrasonic tissue characterization with integrated backscatter offers a promising method for the noninvasive assessment of regional myocardial contractile performance and fibrosis. The aim of this study was to investigate the effect of hemodialysis (HD) on myocardial tissue characterization and left ventricular function in ESRD patients. We examined 26 patients with ESRD undergoing routine HD (age 63 ± 12 years, duration of HD 9.2 ± 3.2 years) and 30 patients with essential hypertension (HT; 60 ± 10 years). Routine echocardiographic parameters and the cyclic variation of ultrasonic integrated backscatter of the ventricular septum (CV-IBS) were measured. Left ventricular mass index was significantly larger in patients with ESRD than in those with HT (217 ± 56 vs 146 ± 45 g/m², P < 0.05). The indices for left ventricular diastolic function (E/A, the ratio of left ventricular peak early to late diastolic filling velocity; DT, the deceleration time of the early diastolic filling) and CV-IBS had deteriorated significantly in patients with ESRD before HD compared with those with HT (E/A, 0.6 ± 0.2 vs 0.9 ± 0.3, P < 0.05; DT, 228 ± 23 vs 184 ± 19 ms, P < 0.05; CV-IBS, 9.0 ± 1.3 vs 12.4 ± 0.9 dB, P < 0.05), possibly reflecting interstitial fibrosis. In patients with ESRD, HD reduced calculated left ventricular mass index by 19% (before HD, 217 ± 56 vs immediately after HD, 176 ± 45 g/m², P < 0.05) and CV-IBS by 19% (9.0 ± 1.3 vs 7.3 ± 1.1 dB, P < 0.05), that possibly reflected improvement of interstitial edema. HD also significantly improved indices for left ventricular diastolic function (E/A, 0.6 ± 0.2 vs 0.9 ± 0.2, P < 0.05; DT, 228 ± 23 vs 188 ± 21 ms, P < 0.05). HD improves myocardial interstitial edema and left ventricular diastolic function in patients with ESRD. Noninvasive assessment of ultrasonic tissue characterization is useful in defining the pathophysiological changes of ventricular myocardium in patients with ESRD. Received: December 17, 2001 / Accepted: April 19, 2002 Correspondence to O. Hirono