Background-Ghrelin is a novel growth hormone-releasing peptide that also induces vasodilation, inhibits sympathetic nerve activity, and stimulates feeding through growth hormone-independent mechanisms. We investigated the effects of ghrelin on left ventricular (LV) function, exercise capacity, and muscle wasting in patients with chronic heart failure (CHF). Methods and Results-Human synthetic ghrelin (2 g/kg twice a day) was intravenously administered to 10 patients with CHF for 3 weeks. Echocardiography, cardiopulmonary exercise testing, dual x-ray absorptiometry, and blood sampling were performed before and after ghrelin therapy. A single administration of ghrelin elicited a marked increase in serum GH (25-fold). Three-week administration of ghrelin resulted in a significant decrease in plasma norepinephrine (1132Ϯ188 to 655Ϯ134 pg/mL; PϽ0.001). Ghrelin increased LV ejection fraction (27Ϯ2% to 31Ϯ2%; PϽ0.05) in association with an increase in LV mass and a decrease in LV end-systolic volume. Treatment with ghrelin increased peak workload and peak oxygen consumption during exercise. Ghrelin improved muscle wasting, as indicated by increases in muscle strength and lean body mass. These parameters remained unchanged in 8 patients with CHF who did not receive ghrelin therapy. Conclusions-These preliminary results suggest that repeated administration of ghrelin improves LV function, exercise capacity, and muscle wasting in patients with CHF.

There is accumulating evidence that vascular inflammation plays critical roles in pathophysiology of atherosclerosis. It is widely accepted that both innate and adaptive immune responses are important for initiation and progression of atherosclerosis, which mainly consist of monocytes, macrophages, neutrophils, T lymphocytes, and B lymphocytes. Moreover, inflammatory biomarkers such as high-sensitivity C-reactive protein and interleukin-6 are known to predict future cardiovascular events, as well as conventional low-density or high-density lipoprotein cholesterol. Thus, current understanding of the inflammatory mechanisms of atherosclerosis have led us to explore novel therapeutic approaches that reducing vascular inflammation itself could lower the rates of critical cardiovascular events. To address the inflammatory hypothesis of atherosclerosis, results of the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) trial have been recently reported that anti-inflammatory therapy using canakinumab, a monoclonal antibody targeting interleukin-1β, significantly reduced recurrent cardiovascular events for secondary prevention of myocardial infarction at high inflammatory risk. In this review, we will first outline the mechanisms of atherosclerosis, especially focusing on their inflammatory aspects. Then we will introduce several critical inflammatory biomarkers that contribute to risk stratification of clinical cardiovascular events. Lastly, we will discuss potentiality and future perspectives of reducing inflammation as a novel therapeutic target for atherosclerotic cardiovascular diseases.

Although many animal studies indicate insulin has cardioprotective effects, clinical studies suggest a link between insulin resistance (hyperinsulinemia) and heart failure (HF). Here we have demonstrated that excessive cardiac insulin signaling exacerbates systolic dysfunction induced by pressure overload in rodents. Chronic pressure overload induced hepatic insulin resistance and plasma insulin level elevation. In contrast, cardiac insulin signaling was upregulated by chronic pressure overload because of mechanical stretch-induced activation of cardiomyocyte insulin receptors and upregulation of insulin receptor and Irs1 expression. Chronic pressure overload increased the mismatch between cardiomyocyte size and vascularity, thereby inducing myocardial hypoxia and cardiomyocyte death. Inhibition of hyperinsulinemia substantially improved pressure overloadinduced cardiac dysfunction, improving myocardial hypoxia and decreasing cardiomyocyte death. Likewise, the cardiomyocyte-specific reduction of insulin receptor expression prevented cardiac ischemia and hypertrophy and attenuated systolic dysfunction due to pressure overload. Conversely, treatment of type 1 diabetic mice with insulin improved hyperglycemia during pressure overload, but increased myocardial ischemia and cardiomyocyte death, thereby inducing HF. Promoting angiogenesis restored the cardiac dysfunction induced by insulin treatment. We therefore suggest that the use of insulin to control hyperglycemia could be harmful in the setting of pressure overload and that modulation of insulin signaling is crucial for the treatment of HF.

Objective-Calorie restriction (CR) prolongs the lifespan of various species, ranging from yeasts to mice. In yeast, CR extends the lifespan by increasing the activity of silencing information regulator 2 (Sir2), an NAD ϩ -dependent deacetylase. SIRT1, a mammalian homolog of Sir2, has been reported to downregulate p53 activity and thereby prolong the lifespan of cells. Although recent evidence suggests a link between SIRT1 activity and metabolic homeostasis during CR, its pathological role in human disease is not yet fully understood. Methods and Results-Treatment of human endothelial cells with high glucose decreases SIRT1 expression and thus activates p53 by increasing its acetylation. This in turn accelerates endothelial senescence and induces functional abnormalities. Introduction of SIRT1 or disruption of p53 inhibits high glucose-induced endothelial senescence and dysfunction. Likewise, activation of Sirt1 prevents the hyperglycemia-induced vascular cell senescence and thereby protects against vascular dysfunction in mice with diabetes. Key Words: cellular senescence Ⅲ p53 Ⅲ diabetes T he NAD ϩ -dependent histone deacetylase Sir2 induces longevity in yeast in response to calorie restriction signals. 1 SIRT1, a mammalian homologue of Sir2 and a member of the Sir2 family called sirtuins, has been shown to target p53, 2-4 Ku70, 5 and the forkhead transcription factors 6 -8 for deacetylation, thereby regulating stress responses, apoptosis, and cellular senescence. Acetylation of p53 is known to be crucial for its stabilization and transcriptional activation. 9 Accumulating evidence suggests that SIRT1 also modulates the metabolism of glucose and fat by interacting with peroxisome proliferator-activated receptor (PPAR) ␥ through nuclear receptor corepressor to repress adipogenesis, 10 modifying PPAR ␥ coactivator-1␣ to regulate hepatic glucose homeostasis 11,12 and regulating insulin secretion levels as well as insulin sensitivity. [13][14][15] Treatment with the sirtuin activator resveratrol has been shown to improve diet-induced obesity and insulin resistance 16,17 and delay age-related deterioration including increased arterial stiffness. 18 Moreover, Sirt1 has been reported to control endothelial angiogenic functions during postnatal vascular growth. 19 However, it remains unclear whether SIRT1 is involved in the pathogenesis of diabetes and its complications including diabetic vasculopathy. Conclusions-TheseVascular cells have a finite lifespan when cultured and eventually undergo senescence. Many of the changes seen in senescent vascular cells are consistent with those that occur in age-related vascular diseases. 20,21 Moreover, senescent vascular cells have been detected in human atherosclerotic tissues and exhibit various functional abnormalities, 22 suggesting that senescence of vascular cells contributes to the pathophysiology of age-related vascular diseases. There is also in vivo evidence for the occurrence of vascular cell senescence in diabetic vasculopathy. 23 Given that CR augments SIRT1 activity...