Yo Koyama

Cardiac-Specific Overexpression of Diacylglycerol Kinase ζ 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 Gqα 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 (DGK&zgr;-TG) mice with cardiac-specific overexpression of DGK&zgr;. There were no differences in heart size and heart weight between DGK&zgr;-TG and wild-type littermate mice. The left ventricular function was normal in DGK&zgr;-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 DGK&zgr;-TG mice, neither translocation of PKC nor upregulation of atrial natriuretic factor gene expression was observed after angiotensin II and phenylephrine infusion. Furthermore, in DGK&zgr;-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 DGK&zgr;-TG mouse hearts, suggesting that DGK&zgr; regulated PKC activity by controlling cellular diacylglycerol levels. Conclusions— These results demonstrated the first evidence that DGK&zgr; negatively regulated the hypertrophic signaling cascade and resultant cardiac hypertrophy in response to GPCR agonists without detectable adverse effects in in vivo hearts.

Soluble Receptor for advanced glycation end products (RAGE) is a prognostic factor for heart failure.

BACKGROUND We recently reported that serum levels of pentosidine, one of the well-defined advanced glycation end products (AGE), was an independent prognostic factor for heart failure. Receptor for AGEs (RAGE) is expressed in a variety of tissues, and RAGE has a C-truncated secretory isoform of the receptor protein, termed soluble RAGE. In the present study, we measured serum soluble RAGE levels in patients and examined whether serum soluble RAGE predicts prognosis in patients with heart failure. METHODS AND RESULTS Serum soluble RAGE concentration was measured in 160 patients with heart failure by a competitive enzyme-linked immunosorbent assay. Patients were prospectively followed during a median follow-up period of 872 days with end points of cardiac death or rehospitalization. Serum soluble RAGE level increased with advancing New York Heart Association functional class. Serum soluble RAGE level was also higher in patients with cardiac events than in event free patients. From the receiver operating characteristic curve analysis, the cutoff value of serum soluble RAGE level was determined as 1220 pg/mL. Kaplan-Meier analysis clearly demonstrated that the high soluble RAGE group had a significantly higher incidence of cardiac events than occurred in the low serum soluble RAGE group (P = .0004). In the multivariate Cox proportional hazard analysis, soluble RAGE and serum pentosidine were independent risk factors for cardiac events (soluble RAGE: HR 1.90, 95% CI 1.16-3.09, P = .010; pentosidine: HR 1.59, 95% CI 1.11-2.29, P = .012). CONCLUSIONS Serum soluble RAGE level is an independent prognostic factor for heart failure, and this novel marker may be useful for risk stratification of patients with heart failure.

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

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.ObjectiveThe aim of the present study was to compare cardiac sympathetic nervous activity assessed by123I-MIBG imaging with serum levels of H-FABP in patients with heart failure.MethodsFifty 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.ResultsHeart to mediastinum (H/M) ratios of123I-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 of123I-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).ConclusionsThese 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.

Pitavastatin inhibits cardiac hypertrophy in a rat model of progressive renal injury.

Increased cardiovascular mortality is an unresolved problem of chronic renal failure. Cardiac hypertrophy, observed in many patients with chronic renal failure, is a major risk factor for cardiovascular death. The purpose of the present study was to examine the effects of pitavastatin on cardiac hypertrophy in a progressive renal injury rat model by subtotal nephrectomy (SNx). Because we previously reported that angiotensin II played a pivotal role in cardiac hypertrophy of SNx rats, we first investigated the effects of pitavastatin on angiotensin II-induced activation of extracellular signal-regulated kinase (ERK) and serum response element (SRE) DNA-binding activity using neonatal rat cardiomyocytes. Angiotensin II-induced ERK activation was attenuated by pretreatment with pitavastatin. Luciferase assay revealed that angiotensin II-induced increase in SRE DNA-binding activity was inhibited by pitavastatin. We next examined the effect of pitavastatin on cardiac hypertrophy of SNx rats in vivo. Treatment with pitavastatin prevented ERK activation and cardiac hypertrophy in SNx rats without changes in blood pressure. The increased expression of atrial natriuretic factor mRNA in SNx rat hearts was significantly attenuated by the treatment with pitavastatin. These results suggest that pitavastatin has a beneficial effect on cardiac hypertrophy in renal failure through preventing the activation of ERK.

Renal dysfunction indicative of outcomes in hospitalized patients with takotsubo syndrome

Background: Left ventricular dysfunction as part of takotsubo syndrome is reversible, and the long-term prognosis appears favorable. However, life-threatening complications are not uncommon during the acute phase, and it remains unclear whether renal dysfunction is a factor in complications suffered by hospitalized patients with takotsubo syndrome. The present study was conducted to investigate the implications of renal dysfunction in this setting. Methods: Data from 61 consecutive patients (male, 21; female, 40) diagnosed with takotsubo syndrome at our hospital between years 2010 and 2016 were evaluated retrospectively. In-hospital complications by definition were all-cause deaths and severe pump failure (Killip class ≥III). Results: Overall, 30 patients (49%) developed renal dysfunction. In the 32 patients (52%) who suffered in-hospital complications (mortality, 10; severe pump failure, 22), estimated glomerular filtration rate (eGFR) was significantly lower by comparison (51.3±29.8 vs. 69.5±29.0; p=0.019). Low eGFR (<30 ml/min per 1.73m2) proved independently predictive of in-hospital complications (hazard ratio =2.84, 95% confidence interval: 1.20–6.69) in multivariate Cox hazard analysis, also showing a significant association with peak event rate of Kaplan–Meier curve (log-rank test, p=0.0073). Similarly, patients with chronic kidney disease were at significantly greater risk of in-hospital complications (hazard ratio=2.49, 95% confidence interval: 1.01–5.98), relative to non-compromised counterparts (eGFR >60 ml/min per 1.73m2). Conclusion: Renal dysfunction is a simple but useful means of predicting complications in hospitalized patients with takotsubo syndrome, especially those with chronic kidney disease.