Celestino Sardu

Calcium release channel RyR2 regulates insulin release and glucose homeostasis

The type 2 ryanodine receptor (RyR2) is a Ca2+ release channel on the endoplasmic reticulum (ER) of several types of cells, including cardiomyocytes and pancreatic β cells. In cardiomyocytes, RyR2-dependent Ca2+ release is critical for excitation-contraction coupling; however, a functional role for RyR2 in β cell insulin secretion and diabetes mellitus remains controversial. Here, we took advantage of rare RyR2 mutations that were identified in patients with a genetic form of exercise-induced sudden death (catecholaminergic polymorphic ventricular tachycardia [CPVT]). As these mutations result in a leaky RyR2 channel, we exploited them to assess RyR2 channel function in β cell dynamics. We discovered that CPVT patients with mutant leaky RyR2 present with glucose intolerance, which was heretofore unappreciated. In mice, transgenic expression of CPVT-associated RyR2 resulted in impaired glucose homeostasis, and an in-depth evaluation of pancreatic islets and β cells from these animals revealed intracellular Ca2+ leak via oxidized and nitrosylated RyR2 channels, activated ER stress response, mitochondrial dysfunction, and decreased fuel-stimulated insulin release. Additionally, we verified the effects of the pharmacological inhibition of intracellular Ca2+ leak in CPVT-associated RyR2-expressing mice, in human islets from diabetic patients, and in an established murine model of type 2 diabetes mellitus. Taken together, our data indicate that RyR2 channels play a crucial role in the regulation of insulin secretion and glucose homeostasis.

Circulating microRNA changes in heart failure patients treated with cardiac resynchronization therapy: responders vs. non-responders

MicroRNAs (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.

Sirtuin 6 Expression and Inflammatory Activity in Diabetic Atherosclerotic Plaques: Effects of Incretin Treatment

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 ± 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-κB 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.

Brief episodes of silent atrial fibrillation predict clinical vascular brain disease in type 2 diabetic patients.

OBJECTIVESnThis study evaluated whether subclinical episodes of atrial fibrillation (AF) were associated with an increased risk of silent cerebral infarct (SCI) and stroke in diabetic patients younger than 60 years who did not have other clinical evidence of AF and cerebrovascular disease at baseline.nnnBACKGROUNDnIn type 2 diabetic patients, one-fourth of strokes are of unknown cause, and subclinical episodes of AF may be a common etiologic factor.nnnMETHODSnA total of 464 type 2 diabetic patients younger than 60 years were included in a longitudinal observational study and matched to patients without diabetes. Patients underwent 48-h electrocardiographic Holter monitoring quarterly to detect brief subclinical episodes of AF (duration of AFxa0<48 h) and were followed up for 37 months. The outcomes were SCI, assessed by magnetic resonance imaging of the brain, and stroke events during the follow-up period.nnnRESULTSnThe prevalence of subclinical episodes of AF was significantly greater among patients with diabetes compared with matched healthy subjects (11% vs. 1.6%, pxa0< 0.0001). During an average duration of 37 months, 43 stroke events occurred in the diabetic population and no events occurred in healthy subjects. Diabetic patients with silent episodes of AF (nxa0= 176) had a higher baseline prevalence of SCI (61% vs. 29%; pxa0< 0.01) and a higher number of stroke events (17.3% vs. 5.9%; pxa0< 0.01) during the follow-up period than the other patients (nxa0= 288). An episode of silent AF was an independent determinant of SCI (odds ratio: 4.441; pxa0< 0.001; confidence interval: 2.42 to 8.16) and an independent predictor of the occurrence of stroke in diabetic patients (hazard ratio: 4.6; pxa0< 0.01; confidence interval: 2.7 to 9.1).nnnCONCLUSIONSnSubclinical episodes of AF occurred frequently in type 2 diabetic patients and were associated with a significantly increased risk of SCI and stroke.

Impact of Diabetes Mellitus on the Clinical Response to Cardiac Resynchronization Therapy in Elderly People

Heart failure (HF) and type 2 diabetes mellitus (T2DM) exhibit a well-established interrelationship and a growing prevalence, in particular in elderly people. Cardiac resynchronization therapy (CRT) has been shown to improve myocardial function in patients with HF and cardiac dyssynchrony. However, reports on CRT in diabetic elderly patients are limited and controversial. Therefore, the aim of the present study was to investigate the functional role of T2DM on the effectiveness of CRT at advanced age. In this single-center prospective study, we enrolled 72 HF patients over 75xa0years old with and without T2DM who underwent CRT implant. Detailed clinical and instrumental data, including cardiac ultrasound analysis, 6-min walk test, and quality-of-life evaluation, were collected at baseline and at 1-year follow-up. At the time of implantation, 44.4xa0% of patients had T2DM, of which 62.5xa0% were well controlled with diet and hypoglycemic drugs and 37.5xa0% were treated by insulin therapy. After 1xa0year, CRT improved myocardial ventricular geometry and functional capacity in a comparable proportion of diabetic and non-diabetic patients alongside with a similar amelioration in the functional status. Taken together, our findings demonstrate that diabetic patients >75xa0years old exhibit a response to CRT that is comparable to non-diabetic subjects.

Functional role of miRNA in cardiac resynchronization therapy

Heart failure (HF) disease progression is related to numerous adaptive processes including cardiac fibrosis, hypertrophy and apoptosis by activation of the fetal gene program and downregulation of mRNA signatures, suggesting the importance of molecular mechanisms that suppress mRNA steady-state levels. miRNAs (miRs) are small, noncoding RNAs that bind mRNAs at their 3-UTRs, leading to mRNA degradation or inhibition of protein translation. Several miRs are unregulated in response to cellular stress and can modify cellular functions such as proliferation, differentiation and programmed death; these miRs are also regulated in cardiac disease. Cardiac resynchronization therapy improves cardiac performance and myocardial mechanical efficiency. In this updated critical appraisal we report on the main miRs that play a key role in response to cardiac resynchronization therapy (i.e., responder vs nonresponder HF patients), focusing on the miR-mediated modulation of cardiac angiogenesis, apoptosis, fibrosis and membrane ionic currents.

Metabolic syndrome is associated with a poor outcome in patients affected by outflow tract premature ventricular contractions treated by catheter ablation

BackgroundThe purpose of this study was to investigate the impact of metabolic syndrome (MS) on outcome of catheter ablation (CA) for treatment of frequent premature ventricular contraction beats (PVCs) originating from right ventricular outflow tract (RVOT), left ventricular outflow tract (LVOT) or coronary cusps (CUSPs), in patients with normal ventricular systolic function and absence of cardiac structural disease.MethodsIn this multicentre prospective study we evaluated 90 patients with frequent PVCs originating from RVOT (nu2009=u200968), LVOT (nu2009=u200919) or CUSPs (nu2009=u20093), treated with CA. According to baseline diagnosis they were divided in patients with MS (nu2009=u200924) or without MS (nu2009=u200966). The study endpoint was a composite of recurrence of acute or delayed outflow tract ventricular arrhythmia: acute spontaneous or inducible outflow tract ventricular arrhythmia recurrence or recurrence of outflow tract PVCs in holter monitoring at follow up.ResultsPatients with MS compared to patients without MS showed a higher acute post-procedural recurrence of outflow tract PVCs (nu2009=u20098, 66.6%, vs. nu2009=u20096, 9.0%, pu2009=u20090.005). At a mean follow up of 35 (17-43) months survival free of recurrence of outflow tract PVCs was lower in patients with baseline MS compared to patients without MS diagnosis (log-rank test, pu2009<u20090.001). In cox regression analysis, only MS was independently associated with study endpoint (HRu2009=u20099.655 , 95% CI 3.000-31.0.68 , pu2009<u20090.001).ConclusionsMS is associated with a higher recurrence rate of outflow tract PVCs after CA in patients without structural heart disease.

Autonomic dysfunction is associated with brief episodes of atrial fibrillation in type 2 diabetes.

BACKGROUND AND AIMSnThis study aimed to investigate the relationship between asymptomatic episodes of atrial fibrillation (AF) and abnormalities of the autonomic nervous system in type 2 diabetic patients who did not have evidence of atrial fibrillation at baseline.nnnMETHODS AND RESULTSnIn a multicentric cross-sectional controlled study, 1992 patients with type 2 diabetes were screened. All underwent ambulatory ECG recording for 48-hour at 3, 6, 9, and 12months. Heart rate variability (HRV) was used as indicator of autonomic activity. One hundred seventy-six diabetics with silent atrial fibrillation episodes (SAFE group) and 288 without silent atrial fibrillation (non-SAFE group) were enrolled. These selected diabetics were matched on clinical and anthropometric data to 120 control subjects without diabetes of the control group. HRV analysis evidenced that LF/HF ratio was significantly higher in the SAFE group than in the non-SAFE group (P<0.05) in the whole period of HM analysis. AF absolute burdens were positively correlated with LF/HF ratio (r=0.31, P<0.001). Multiple regression analysis showed that LF/HF ratio was an independent determinant of AF episodes.nnnCONCLUSIONSnThis study originally showed a strong relationship between autonomic dysfunction and silent atrial fibrillation in type 2 diabetes.

Effects of α-lipoic acid therapy on sympathetic heart innervation in patients with previous experience of transient takotsubo cardiomyopathy.

BACKGROUNDnTakotsubo syndrome is a stress cardiomyopathy, characterized by reversible left ventricle (LV) apical ballooning in the absence of significant angiographic coronary artery stenosis. The frequent association with emotional stress suggests in this disease an autonomic nervous system involvement. We could think that a therapeutic treatment targeting heart sympathetic dysfunction could be of crucial importance.nnnMETHODSnFrom January 2010 to June 2012, 886 patients were consecutively evaluated at Cardarelli Hospital, Naples, Italy. Among these, 48 patients met takotsubo cardiomyopathy (TCM) criteria. Each patient was assessed with history and physical examination, 12-lead electrocardiogram, serum troponin, coronary arteriography, and left ventricular angiogram, perfusion myocardial scintigraphy with technetium 99m, with echocardiography and 123I-metaiodobenzylguanidine (MIBG) myocardial scintigraphy. At discharge, the surviving patients were randomly assigned to α-lipoic acid (ALA) treatment (600mg once daily) or placebo. Following discharge, after the initial TCM event, patients returned to our outpatient clinic at Internal Medicine of the Second University Naples for the follow-up evaluation quarterly until 12 months. Routine analysis, myocardial damage serum markers, oxidative stress serum markers, pro-inflammatory cytokines, and sympathetic tone activity were evaluated in all patients.nnnRESULTSnALA administration improved MIBG defect size at 12 months compared to placebo.nnnCONCLUSIONSnAdrenergic cardiac innervation dysfunction in TCM patients persists after previous experience of transient stress-induced cardiac dysfunction. ALA treatment improves the adrenergic cardiac innervation. This study evaluates whether sympatho-vagal alterations are TCM event-related.

Telemonitoring in heart failure patients treated by cardiac resynchronisation therapy with defibrillator (CRT-D): the TELECART Study.

Telemonitoring (TM) is a safe and efficient monitoring system for internal cardioverter defibrillator device (ICD) recipients. TM has been used to track info on the clinical status of heart failure patients treated by ICD and/or cardiac resynchronisation therapy defibrillator (CRT‐D). The aim of this study was to investigate the impact of TM on clinical outcomes in a population of CRT‐D patients with heart failure.