AimsMicroRNAs (miRNAs) play an important role in the pathogenesis of structural alterations of the failing heart through their ability to regulate negatively the expression levels of genes that govern the process of adaptive and maladaptive cardiac remodelling. We studied whether LV reverse remodelling after CRT was associated with changes of circulating miRNAs in patients with heart failure (HF) and dyssynchrony. Methods and resultsA prospective, non-randomized self-control trial was performed in 81 patients with HF eligible for CRT. At baseline, to select the HF miRNA profile, we evaluated the expression of 84 miRNAs (implicated in the pathogenesis of structural alterations of the failing heart) in three groups of patients: healthy subjects (healthy group, n ¼ 15); patients with HF (HF group, n ¼ 81); and patients without HF matched for age, sex, and concomitant disease with HF patients (control group, n ¼ 60). At 12 months, the selected miRNA profile was evaluated in plasma from responder (n ¼ 55) and non-responder HF patients (n ¼ 26) to CRT. In the test cohort, the HF patients were characterized by lower expression of 48 miRNAs (all P , 0.04) as compared with healthy subjects. In the validation cohort, the HF patients were characterized by lower expression of 24 miRNAs (all P , 0.03) as compared with control patients. At 12 months, 55 patients (68%) were considered responders and 26 non-responders to CRT (32%). Responders showed an increase in expression of 19 miRNAs (all P , 0.03) compared with baseline expression, whereas in the non-responders we observed an increase of six miRNAs (all P , 0.05) compared with baseline expression. At follow-up, miRNAs were differentially expressed between responders and non-responders. The responders were characterized by higher expression of five miRNAs (miRNA-26b-5p, miRNA-145-5p, miRNA-92a-3p, miRNA-30e-5p, and miRNA-29a-3p; P , 0.01 for all) as compared with non-responders. ConclusionsIn responders, reverse remodelling is associated with favourable changes in miRNAs that regulate cardiac fibrosis, apoptosis, and hypertrophy.--

The role of sirtuin 6 (SIRT6) in atherosclerotic progression of diabetic patients is unknown. We evaluated SIRT6 expression and the effect of incretin-based therapies in carotid plaques of asymptomatic diabetic and nondiabetic patients. Plaques were obtained from 52 type 2 diabetic and 30 nondiabetic patients undergoing carotid endarterectomy. Twenty-two diabetic patients were treated with drugs that work on the incretin system, GLP-1 receptor agonists, and dipeptidyl peptidase-4 inhibitors for 26 6 8 months before undergoing the endarterectomy. Compared with nondiabetic plaques, diabetic plaques had more inflammation and oxidative stress, along with a lesser SIRT6 expression and collagen content. Compared with non-GLP-1 therapy-treated plaques, GLP-1 therapy-treated plaques presented greater SIRT6 expression and collagen content, and less inflammation and oxidative stress, indicating a more stable plaque phenotype. These results were supported by in vitro observations on endothelial progenitor cells (EPCs) and endothelial cells (ECs). Indeed, both EPCs and ECs treated with high glucose (25 mmol/L) in the presence of GLP-1 (100 nmol/L liraglutide) presented a greater SIRT6 and lower nuclear factor-kB expression compared with cells treated only with high glucose. These findings establish the involvement of SIRT6 in the inflammatory pathways of diabetic atherosclerotic lesions and suggest its possible positive modulation by incretin, the effect of which is associated with morphological and compositional characteristics of a potential stable plaque phenotype.Cardiovascular disease represents the leading cause of death in patients with type 2 diabetes (1). Diabetes leads to increased vulnerability for plaque disruption, and mediates increased incidence and severity of clinical events (2). Inflammation, particularly in diabetes, plays a central role in the cascade of events that result in plaque erosion and fissuring (2). There is now increasing evidence that a number of transcription factors, including the Sir2 family of enzymes, namely sirtuins (SIRTs), regulate multiple genes whose products are putatively involved in the regulation of inflammation and endothelial cell (EC) function (3). The Sir2 family consists of seven enzymes (SIRT1 to SIRT7) that share a conserved core catalytic domain, but differ in their cellular localization and tissue distribution (4). Among the SIRTs, SIRT6, a chromatinassociated deacetylase, is considered to have a leading role in regulating genomic stability, cellular metabolism, stress response, and aging (5-8). A recent study (9) in mice suggested a role for SIRT6 in inflammation. Moreover, the knockdown of SIRT6 resulted in the increased expression of proinflammatory cytokines (interleukin [IL]-1b, IL-6, and IL-8), extracellular matrix remodeling enzymes (matrix metalloproteinase [MMP]-2, MMP-9, and plasminogen activator inhibitor 1), and intracellular adhesion molecule-1 (4). In ECs, the loss of SIRT6 was associated with an increased expression of nuclear factor-kB (NF-kB), whereas o...

A prolonged heart rate-adjusted QT (corrected QT interval: QTc) is a risk factor for sudden death in patients with the long QT syndrome [1], patients with myocardial infarction [2], subjects referred for Holter monitoring [3] and healthy men and women [4±5]. A prolonged QTc interval has been reported in diabetic patients with autonomic neuropathy [6] and is associated with an increased mortality risk in nephropathic Type I (insulin-dependent) diabetic patients [7], as well as with fasting and post-challenge glucose concentrations in elderly people [8]. Moreover, an association of post-load insulin concentrations with QTc dispersion has been reported in a series of healthy subjects during oral glucose testing [9].A recent epidemiologic study in Type II (non-insulin-dependent) diabetic patients shows that the prevalence of QTc prolongation is as high as 26 % and is associated with heart disease [10].The aims of our study were to evaluate the effect of acute hyperglycaemia on haemodynamic variables, as well as QTc duration and QTc dispersion in normal subjects, and to dissect the effects of hyperglycaemia from those of hyperinsulinaemia by blocking the release of endogenous insulin with octreotide, a somatostatin analogue. AbstractAims/hypothesis. Prolongation of heart rate-adjusted QT (QTc) is associated with an increased risk of coronary heart disease and sudden death. The objective of this study was to investigate whether acute increases of plasma glucose concentrations in healthy subjects could influence QTc and QTc dispersion. Methods. Plasma glucose concentrations were quickly raised to 15 mmol/l in 20 healthy subjects (10 men/ 10 women) and maintained for 2 h. On another occasion, and in random order, all subjects underwent the same hyperglycaemic clamp as above and an infusion of the somatostatin analogue octreotide (25 mg as iv bolus followed by a 0.5 g/min infusion) to block the release of endogenous insulin. Results. Systolic and diastolic blood pressures, heart rate and plasma catecholamine concentrations showed significant increases (p < 0.05) starting after 60 min of hyperglycaemia. QTc, QTc dispersion and PR interval also showed significant increments at 120 min of the hyperglycaemic clamp. The infusion of octreotide did not influence QTc duration, QTc dispersion, PR interval and the haemodynamic effects of acute hyperglycaemia. Conclusion/interpretation. The results show that acute hyperglycaemia produces significant increments of QTc and QTc dispersion in normal subjects. In this context, endogenously released insulin during acute hyperglycaemia seems to play a minor part.

OBJECTIVE -Obesity is an important risk factor for heart failure in both women and men. Dyssynchrony between right and left ventricular contraction and relaxation has been identified as an independent predictor of heart failure. We examined the relationship of ventricular synchronization abnormalities with the concentration of proinflammatory cytokines in obese women at baseline and after sustained weight loss.RESEARCH DESIGN AND METHODS -Echocardiographic parameters of ventricular dyssynchrony, circulating levels of tumor necrosis factor (TNF)-␣, interleukin (IL)-6, IL-18, and C-reactive protein (CRP) were investigated in 67 healthy, premenopausal obese women and 40 age-matched normal-weight women.RESULTS -Compared with nonobese women, obese women had increased concentrations of CRP (P Ͻ 0.01), TNF-␣ (P Ͻ 0.01), IL-6 (P Ͻ 0.01), and IL-18 (P Ͻ 0.01). Moreover, obese women had a higher myocardial performance index (P Ͻ 0.02) and lower transmitral Doppler flow (P Ͻ 0.05), pulmonary venous flow analysis (P Ͻ 0.02), and ejection fraction (P Ͻ 0.05), indicating ventricular dyssynchrony. Concentrations of CRP, TNF-␣, and IL-6 were related to anthropometric indexes of obesity and to echocardiographic parameters of ventricular dyssynchrony. After 1 year of a multidisciplinary program of weight reduction, obese women lost at least 10% of their original weight. This was associated with reduction of cytokine (P Ͻ 0.01) and CRP (P Ͻ 0.02) concentrations and with improvement of echocardiographic parameters of ventricular dyssynchrony, which correlated with changes in adiposity, particularly visceral adiposity.CONCLUSIONS -In obese women, ventricular dyssynchrony correlates with body fat, possibly through inappropriate secretion of cytokines. Weight loss represents a safe method for downregulating the inflammatory state and ameliorating cardiac function in obese women. Diabetes Care 27:47-52, 2004D yssynchrony between right and left ventricular contraction and relaxation has been identified as an independent predictor of cardiac mortality in patients with heart failure (1,2). Moreover, cardiac resynchronization reduces mortality from progressive heart failure in patients with symptomatic left ventricular dysfunction and ventricular dyssynchrony (3). Because approximately onehalf of all deaths among patients with heart failure occur because of progressive cardiac dysfunction, it may be important to evaluate heart function among people at risk of heart failure.Obesity is an important risk factor for heart failure in both women and men. Approximately 11 and 14% of heart failure cases among men and women in the community, respectively, are attributable to increased BMI (4). This is associated with altered left ventricular remodeling, possibly owing to increased hemodynamic load, neurohormonal activation, and increased cytokine production (5). Adipocytes synthesize and secrete several cytokines, including tumor necrosis factor (TNF)-␣ (6) and interleukin (IL)-6 (7). Elevated levels of IL-6, TNF-␣, and IL-18 as well as the sensiti...

This article is available online at http://www.jlr.org tural basis of the progression from well-compensated hypertrophy to HF is still largely unknown in MS patients. Emerging evidence suggests that inherited and acquired cardiomyopathies, such as impaired glucose tolerance and diabetes, are associated with marked intracellular lipid accumulation in the heart ( 2, 3 ). In the normal body, most triglyceride is stored in adipocytes; the amount of triglyceride stored in nonadipocyte tissues (liver, and myocardium) is minimal and very tightly regulated. However, several-fold increased cardiomyocyte triglyceride stores are observed in animal models of obesity and diabetes ( 4 ). This lipid accumulation may contribute to cardiomyocyte death by nonoxidative and oxidative ( 5 ) metabolic pathways and to HF. Even in humans, myocardial lipid content was recently reported to increase with the degree of adiposity and contribute to cardiac dysfunction ( 6 ), suggesting that myocardial lipid content may be a biomarker and putative therapeutic target for cardiac disease in patients with MS.Genes involved in lipid metabolism are nutritionally regulated at the transcriptional level in a coordinated fashion ( 7 ). Sterol-regulatory element binding protein (SREBP)-1c is a transcription factor that controls lipogenesis and is induced during overnutrition to facilitate the conversion of glucose to fatty acids and triglycerides for the storage of excess energy ( 8 ). Uncontrolled activation of nuclear SREBP-1c in the liver can cause hepatosteatosis Metabolic syndrome (MS) is strongly associated with left ventricular (LV) hypertrophy and cardiac function derangements that lead to heart failure (HF) ( 1 ). The struc-

OBJECTIVE -Stress hyperglycemia has been associated with increased mortality in patients with myocardial infarction (MI). We examined the association between plasma glucose levels, circulating inflammatory markers, T-cell activation, and functional cardiac outcome in patients with first MI. RESEARCH DESIGN AND METHODS -Echocardiographic parameters, circulating levels of interleukin-18 (IL-18), C-reactive protein (CPR), and the percent of CD16-CD56, CD4/CD8, CD152, and HLA-DR expression were investigated in 108 patients with acute MI on admission to the emergency ward.RESULTS -Our review found that 31 new hyperglycemic patients (glycemia Ն7 mmol/l) had higher infarct segment length (P Ͻ 0.05) and myocardial performance index (P Ͻ 0.02) and reduced transmitral Doppler flow (P Ͻ 0.05), pulmonary flow analysis (P Ͻ 0.02), and ejection fraction (P Ͻ 0.05) compared with 36 hyperglycemic diabetic patients and 41 normoglycemic patients. Plasma IL-18 and CRP were higher in the hyperglycemic than in the normoglycemic patients (P Ͻ 0.005), with the highest values in patients with new hyperglycemia (P Ͻ 0.05). Hyperglycemic patients had a higher percent of CD16ϩ/CD56ϩ cells and CD4/CD8 ratio (P Ͻ 0.01), whereas they had lower CD152 expression (which has a negative regulatory function in T-cell activation) compared with normoglycemic patients (P Ͻ 0.001).CONCLUSIONS -During MI, hyperglycemia is associated with increased levels of inflammatory markers, enhanced expression of cytotoxic T-cells, and reduced expression of T-cells, which are implicated in limiting the immune process. An increased inflammatory immune process seems a likely mechanism linking acute hyperglycemia to poor cardiac outcome in MI patients. Diabetes Care 26:3129 -3135, 2003A n unusually high prevalence of glycosuria in nondiabetic patients who have acute myocardial infarction (MI) was noted as early as 1931 (1). Stress hyperglycemia after MI is associated with an increased risk of in-hospital mortality in patients with and without diabetes (2). Moreover, a positive association between hyperglycemia at the time of the event and subsequent mortality from MI has been reported (3). Although the mechanisms underlying this association are not fully understood, evidence that the use of insulin to lower glucose concentrations decreases mortality in diabetic patients who have MI (4) suggests that hyperglycemia is not simply an epiphenomenon of a stress response. Consequently, hyperglycemia at the time of MI may be an important and potentially modifiable risk factor for poor outcome.A growing body of evidence suggests that MI is associated with local and systemic inflammation (5). Cell activation, which is mediated to some extent by immune mechanisms, is an important component of inflammatory reaction (6). Atherosclerotic plaques contain large numbers of activated T-cells, suggesting that immune mechanisms are important factors in the pathogenesis of the atherosclerotic background (6). Indeed, inflammatory cells infiltrate nearly all plaques, and culprit lesions of...

Erectile dysfunction (ED) is a common complication and an important cause of decreased quality of life in men with diabetes. These patients present a risk of ED three-fold higher than the general population; the prevalence of ED increases with age, but in diabetic men it can occur 10 to 15 years earlier regardless of their insulin dependency status [1].The causes of ED in diabetic patients can be multifactorial, involving mainly vascular, neurological and Diabetologia (2001) AbstractAims/hypothesis. The aim of this study was to evaluate the relation between erectile dysfunction and endothelial functions, coagulation activation, peripheral and autonomic neuropathy in men with Type II (non-insulin-dependent) diabetes mellitus. Methods. We studied 30 Type II diabetic patients with symptomatic erectile dysfunction and 30 potent diabetic patients matched for age and disease. Endothelial functions were assessed with the l-arginine test, plasma thrombomodulin and cell adhesion molecules circulating concentrations. Haemostasis was evaluated with markers of thrombin activation and fibrinolysis. Quantitative sensory testing (vibratory, warming, and heat-pain thresholds), cardiovascular reflex tests and 24-h blood pressure monitoring were used to assess peripheral or autonomic neuropathy. Results. Mean erectile score and HbA 1 c were 10.5 5.8 and 8.3 1.6 % in patients with erectile dysfunction, and 24.0 0.7 and 6.8 1.4 % in those without erectile dysfunction, respectively (p < 0.001); there was a significant relation between HbA 1 c and erectile function score in patients with erectile dysfunction (r = ±0.45, p = 0.02). The decrease in blood pressure and platelet aggregation in response to l-arginine was lower (p < 0.05±0.02) in patients with erectile dysfunction, whereas soluble thrombomodulin, P-selectin and intercellular cell ahhesion molecule-1 concentrations were higher (p < 0.05±0.02). Indices of coagulation activation (F1 + 2 and d-dimers) and reduced fibrinolysis (PAI-1) were also found to be higher in erectile dysfunction patients. Heat-pain and warm perception thresholds, as well as cardiovascular reflex tests, were most commonly abnormal in patients with erectile dysfunction (p < 0.05). In multivariate analysis, HbA 1 c , MBP response to l-arginine, P-selectin, indices of coagulation, and quantitative sensory testing were independent predictors of erectile function score. Conclusion/interpretation. Erectile dysfunction in diabetic men correlates with endothelial dysfunction. A reduced nitric oxide activity might provide a unifying explanation. [Diabetologia (2001

In subjects with diabetes, red wine consumption, taken with meals, significantly reduces oxidative stress and pro-inflammatory cytokines as well as improving cardiac function after MI. Moderate red wine intake with meals may have a beneficial effect in the prevention of cardiovascular complications after MI in subjects with diabetes.