Isolated Valve Amyloid Deposition in Aortic Stenosis: Potential Clinical and Pathophysiological Relevance.

Amyloid deposition within stenotic aortic valves (AVs) also appears frequent in the absence of cardiac amyloidosis, but its clinical and pathophysiological relevance has not been investigated. We will elucidate the rate of isolated AV amyloid deposition and its potential clinical and pathophysiological significance in aortic stenosis (AS). In 130 patients without systemic and/or cardiac amyloidosis, we collected the explanted AVs during cardiac surgery: 57 patients with calcific AS and 73 patients with AV insufficiency (41 with AV sclerosis and 32 without, who were used as controls). Amyloid deposition was found in 21 AS valves (37%), 4 sclerotic AVs (10%), and none of the controls. Patients with and without isolated AV amyloid deposition had similar clinical and echocardiographic characteristics and survival rates. Isolated AV amyloid deposition was associated with higher degrees of AV fibrosis (p = 0.0082) and calcification (p < 0.0001). Immunohistochemistry analysis suggested serum amyloid A1 (SAA1), in addition to transthyretin (TTR), as the protein possibly involved in AV amyloid deposition. Circulating SAA1 levels were within the normal range in all groups, and no difference was observed in AS patients with and without AV amyloid deposition. In vitro, AV interstitial cells (VICs) were stimulated with interleukin (IL)-1ß which induced increased SAA1-mRNA both in the control VICs (+6.4 ± 0.5, p = 0.02) and the AS VICs (+7.6 ± 0.5, p = 0.008). In conclusion, isolated AV amyloid deposition is frequent in the context of AS, but it does not appear to have potential clinical relevance. Conversely, amyloid deposition within AV leaflets, probably promoted by local inflammation, could play a role in AS pathophysiology.

Epicardial Adipose Tissue and Cardiac Arrhythmias: Focus on Atrial Fibrillation.

Atrial Fibrillation (AF) is the most frequent cardiac arrhythmia and its prevalence increases with age. AF is strongly associated with an increased risk of stroke, heart failure and cardiovascular mortality. Among the risk factors associated with AF onset and severity, obesity and inflammation play a prominent role. Numerous recent evidence suggested a role of epicardial adipose tissue (EAT), the visceral fat depot of the heart, in the development of AF. Several potential arrhythmogenic mechanisms have been attributed to EAT, including myocardial inflammation, fibrosis, oxidative stress, and fat infiltration. EAT is a local source of inflammatory mediators which potentially contribute to atrial collagen deposition and fibrosis, the anatomical substrate for AF. Moreover, the close proximity between EAT and myocardium allows the EAT to penetrate and generate atrial myocardium fat infiltrates that can alter atrial electrophysiological properties. These observations support the hypothesis of a strong implication of EAT in structural and electrical atrial remodeling, which underlies AF onset and burden. The measure of EAT, through different imaging methods, such as echocardiography, computed tomography and cardiac magnetic resonance, has been proposed as a useful prognostic tool to predict the presence, severity and recurrence of AF. Furthermore, EAT is increasingly emerging as a promising potential therapeutic target. This review aims to summarize the recent evidence exploring the potential role of EAT in the pathogenesis of AF, the main mechanisms by which EAT can promote structural and electrical atrial remodeling and the potential therapeutic strategies targeting the cardiac visceral fat.

Epicardial Adipose Tissue-Derived IL-1ß Triggers Postoperative Atrial Fibrillation.

Background and aims: Post-operative atrial fibrillation (POAF), defined as new-onset AF in the immediate period after surgery, is associated with poor adverse cardiovascular events and a higher risk of permanent AF. Mechanisms leading to POAF are not completely understood and epicardial adipose tissue (EAT) inflammation could be a potent trigger. Here, we aim at exploring the link between EAT-secreted interleukin (IL)-1ß, atrial remodeling, and POAF in a population of coronary artery disease (CAD) patients. Methods: We collected EAT and atrial biopsies from 40 CAD patients undergoing cardiac surgery. Serum samples and EAT-conditioned media were screened for IL-1ß and IL-1ra. Atrial fibrosis was evaluated at histology. The potential role of NLRP3 inflammasome activation in promoting fibrosis was explored in vitro by exposing human atrial fibroblasts to IL-1ß and IL-18. Results: 40% of patients developed POAF. Patients with and without POAF were homogeneous for clinical and echocardiographic parameters, including left atrial volume and EAT thickness. POAF was not associated with atrial fibrosis at histology. No significant difference was observed in serum IL-1ß and IL-1ra levels between POAF and no-POAF patients. EAT-mediated IL-1ß secretion and expression were significantly higher in the POAF group compared to the no-POAF group. The in vitro study showed that both IL-1ß and IL-18 increase fibroblasts' proliferation and collagen production. Moreover, the stimulated cells perpetuated inflammation and fibrosis by producing IL-1ß and transforming growth factor (TGF)-ß. Conclusion: EAT could exert a relevant role both in POAF occurrence and in atrial fibrotic remodeling.

Inflammation and Cardiovascular Diseases in the Elderly: The Role of Epicardial Adipose Tissue.

Human aging is a complex phenomenon characterized by a wide spectrum of biological changes which impact on behavioral and social aspects. Age-related changes are accompanied by a decline in biological function and increased vulnerability leading to frailty, thereby advanced age is identified among the major risk factors of the main chronic human diseases. Aging is characterized by a state of chronic low-grade inflammation, also referred as inflammaging. It recognizes a multifactorial pathogenesis with a prominent role of the innate immune system activation, resulting in tissue degeneration and contributing to adverse outcomes. It is widely recognized that inflammation plays a central role in the development and progression of numerous chronic and cardiovascular diseases. In particular, low-grade inflammation, through an increased risk of atherosclerosis and insulin resistance, promote cardiovascular diseases in the elderly. Low-grade inflammation is also promoted by visceral adiposity, whose accumulation is paralleled by an increased inflammatory status. Aging is associated to increase in epicardial adipose tissue (EAT), the visceral fat depot of the heart. Structural and functional changes in EAT have been shown to be associated with several heart diseases, including coronary artery disease, aortic stenosis, atrial fibrillation, and heart failure. EAT increase is associated with a greater production and secretion of pro-inflammatory mediators and neuro-hormones, so that thickened EAT can pathologically influence, in a paracrine and vasocrine manner, the structure and function of the heart and is associated to a worse cardiovascular outcome. In this review, we will discuss the evidence underlying the interplay between inflammaging, EAT accumulation and cardiovascular diseases. We will examine and discuss the importance of EAT quantification, its characteristics and changes with age and its clinical implication.

Red Flags, Prognostic Impact, and Management of Patients With Cardiac Amyloidosis and Aortic Valve Stenosis: A Systematic Review and Meta-Analysis.

Background: Cardiac amyloidosis (CA) has been recently recognized as a condition frequently associated with aortic stenosis (AS). The aim of this study was to evaluate: the main characteristics of patients with AS with and without CA, the impact of CA on patients with AS mortality, and the effect of different treatment strategies on outcomes of patients with AS with concomitant CA. Materials and Methods: A detailed search related to CA in patients with AS and outcomes was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Seventeen studies enrolling 1,988 subjects (1,658 AS alone and 330 AS with CA) were included in the qualitative and quantitative analysis of main patients with AS characteristics with and without CA, difference in mortality, and treatment strategy. Results: The prevalence of CA resulted in a mean of 15.4% and it was even higher in patients with AS over 80 years old (18.2%). Patients with the dual diagnosis were more often males, had lower body mass index (BMI), were more prone to have low flow, low gradient with reduced left ventricular ejection fraction AS phenotype, had higher E/A and E/e', and greater interventricular septum hypertrophy. Lower Sokolow-Lyon index, higher QRS duration, higher prevalence of right bundle branch block, higher levels of N-terminal pro-brain natriuretic peptide, and high-sensitivity troponin T were significantly associated with CA in patients with AS. Higher overall mortality in the 178 patients with AS + CA in comparison to 1,220 patients with AS alone was observed [odds ratio (OR) 2.25, p = 0.004]. Meta-regression analysis showed that younger age and diabetes were associated with overall mortality in patients with CS with CA (Z-value -3.0, p = 0.003 and Z-value 2.5, p = 0.013, respectively). Finally, patients who underwent surgical aortic valve replacement (SAVR) or transcatheter aortic valve implantation (TAVI) had a similar overall mortality risk, but lower than medication-treated only patients. Conclusion: Results from our meta-analysis suggest that several specific clinical, electrocardiographic, and echocardiographic features can be considered "red flags" of CA in patients with AS. CA negatively affects the outcome of patients with AS. Patients with concomitant CA and AS benefit from SAVR or TAVI.

Epicardial Adipose Tissue and Postoperative Atrial Fibrillation.

BACKGROUND: Atrial fibrillation (AF) often occurs after cardiac surgery and is associated with increased risk of stroke and mortality. Prior studies support the important role of inflammation in the pathogenesis of postoperative atrial fibrillation (POAF). It is known that an increased volume and a pro-inflammatory phenotype of epicardial adipose tissue (EAT) are both associated with AF onset in non surgical context. In the present study, we aim to evaluate whether also POAF occurrence may be triggered by an increased production of inflammatory mediators from EAT. METHODS: The study population was composed of 105 patients, with no history of paroxysmal or permanent AF, undergoing elective cardiac surgery. After clinical evaluation, all patients performed an echocardiographic study including the measurement of EAT thickness. Serum samples and EAT biopsies were collected before surgery. Levels of 10 inflammatory cytokines were measured in serum and EAT conditioned media. After surgery, cardiac rhythm was monitored for 7 days. RESULTS: Forty-four patients (41.3%) developed POAF. As regard to cardiovascular therapy, only statin use was significantly lower in POAF patients (65.1% vs. 84.7%; p-0.032). Levels of Monocyte Chemoattractant Protein-1 (MCP-1), in both serum and EAT, were significantly higher in POAF patients (130.1 pg/ml vs. 68.7 pg/ml; p = <0.001; 322.4 pg/ml vs. 153.4 pg/ml; p = 0.028 respectively). EAT levels of IL-6 were significantly increased in POAF patients compared to those in sinus rhythm (SR) (126.3 pg/ml vs. 23 pg/ml; p = <0.005). CONCLUSION: Higher EAT levels of IL-6 and MCP-1 are significantly associated with the occurrence of POAF. Statin therapy seems to play a role in preventing POAF. These results might pave the way for a targeted use of these drugs in the perioperative period.

The elderly at risk: aldosterone as modulator of the immune response to SARS-CoV-2 infection.

The elderly population is the most susceptible to SARS-CoV-2 infection and develops the worst clinical phenotype with severe pneumonia and cardiac complications. Older COVID-19 patients are also at higher risk of sudden death, mainly attributable to electrolyte disorders and to an uncontrolled inflammatory response. After the identification of ACE 2 as the receptor of SARS-CoV-2 in human cells, several research studies have focused on the role of the activation of Renin Angiotensin System in COVID-19 clinical course. In the present opinion paper, we discuss the role of hyperaldosteronism in the increasing risk of cardiac complications in COVID-19 older patients. In particular, we focus on the immunoregulatory activity of aldosterone, as the last mediator of the Renin Angiotensin System cascade, in activating the innate and adaptive immune response related to SARS-CoV-2 infection in the elderly. Aldosterone may stimulate dendritic cells and the recruitment of monocytes/macrophages in the endothelium of coronary vessels, favoring the production of pro-inflammatory mediators and T-cells response. Higher basal levels of aldosterone together with SARS-CoV-2-induced production may explain the unfavorable course of COVID-19 in the elderly.

The role of inflammation and metabolic risk factors in the pathogenesis of calcific aortic valve stenosis.

Given the epidemiologic increase of aged population in the world, aortic stenosis (AS) represents now the most common valvular heart disease in industrialized countries. It is a very challenging disease, representing an important cause of morbidity, hospitalization and death in the elderly population. It is widely recognized that AS is the result of a very complex active process, driven by inflammation and involving multifactorial pathological mechanisms promoting valvular calcification and valvular bone deposition. Several evidence suggest that epicardial adipose tissue (EAT), the visceral fat depot of the heart, represents a direct source of cytokines and could mediate the deleterious effects of systemic inflammation on the myocardium. Importantly, obesity and metabolic disorders are associated with chronic systemic inflammation leading to a significant increase of EAT amount and to a pro-inflammatory phenotypic shift of this fat depot. It has been hypothesized that the EAT inflammatory state can influence the structure and function of the heart, thus contributing to the pathogenesis of several cardiac diseases, including calcific AS. The current review will discuss the recently discovered mechanisms involved in the pathogenesis of AS, with particular attention to the role of inflammation, metabolic risk factors and pro-fibrotic and pro-osteogenic signal pathways promoting the onset and progression of the disease. Moreover, it will be explored the potential role of EAT in the AS pathophysiology.

Epicardial Adipose Tissue and IL-13 Response to Myocardial Injury Drives Left Ventricular Remodeling After ST Elevation Myocardial Infarction.

INTRODUCTION: Left ventricular (LV) remodeling after ST-segment elevation myocardial infarction (STEMI) is explained only in part by the infarct size, and the inter-patient variability may be ascribed to different inflammatory response to myocardial injury. Epicardial adipose tissue (EAT) is a source of inflammatory mediators which directly modulates the myocardium. EAT increase is associated to several cardiovascular diseases; however, its response to myocardial injury is currently unknown. Among inflammatory mediators, IL-13 seems to play protective role in LV regeneration, but its variations after STEMI have not been described yet. Purpose: In the present study we analyzed the association between infarct-related changes of EAT and IL-13 in post-STEMI LV remodeling. METHODS: We enrolled 100 patients with STEMI undergoing primary angioplasty. At the enrolment (T0) and after 3 months (T1), we measured EAT thickness by echocardiography and circulating levels of IL-13 by ELISA. RESULTS: At T1, the 60% of patients displayed increased EAT thickness (ΔEAT > 0). ΔEAT was directly associated to LV end-diastolic volume (r = 0.42; p = 0.014), LV end-systolic volume (r = 0.42; p = 0.013) and worse LV ejection fraction (LVEF) at T1 (r = -0.44; p = 0.0094), independently of the infarct size. In the overall population IL-13 levels significantly decreased at T1 (p = 0.0002). The ΔIL-13 was directly associated to ΔLVEF (r = 0.42; p = 0.017) and inversely related to ΔEAT (r = -0.51; p = 0.022), thus suggesting a protective role for IL-13. CONCLUSION: The variability of STEMI-induced "inflammatory response" may be associated to the post-infarct LV remodeling. ΔEAT thickness and ΔIL-13 levels could be novel prognostic markers in STEMI patients.

Imbalance Between Interleukin-1ß and Interleukin-1 Receptor Antagonist in Epicardial Adipose Tissue Is Associated With Non ST-Segment Elevation Acute Coronary Syndrome.

INTRODUCTION: Interleukin-1beta (IL-1ß) is crucially involved in the pathogenesis of coronary atherosclerotic diseases (CAD) and its inhibition has proven cardiovascular benefits. Epicardial adipose tissue (EAT) is a local source of inflammatory mediators which may negatively affect the surrounding coronary arteries. In the present study, we explored the relationship between serum and EAT levels of IL-1ß and IL-1 receptor antagonist (IL-1ra) in patients with chronic coronary syndrome (CCS) and recent acute coronary syndrome (ACS). METHODS: We obtained EAT biopsies in 54 CCS (Group 1) and 33 ACS (Group 2) patients undergoing coronary artery bypass grafting. Serum and EAT levels of IL-1ß and IL-1ra were measured in all patients. An immunophenotypic study was carried out on EAT biopsies and the CD86 events were studied as markers of M1 macrophages. RESULTS: Circulating levels of IL-1ß were significantly higher in the overall CAD population compared to a control group [7.64 pg/ml (6.86; 8.57) vs. 1.89 pg/ml (1.81; 2.29); p < 0.001]. In contrast, no differences were observed for serum IL-1ra levels between CAD and controls. Comparable levels of serum IL-1ß were found between Groups 1 and 2 [7.6 pg/ml (6.9; 8.7) vs. 7.9 pg/ml (7.2; 8.6); p = 0.618]. In contrast, significantly lower levels of serum IL-1ra were found in Group 2 compared to Group 1 [274 pg/ml (220; 577) vs. 603 pg/ml (334; 1022); p = 0.035]. No differences of EAT levels of IL-1ß were found between Group 2 and Group 1 [3.4 pg/ml (2.3; 8.4) vs. 2.4 pg/ml (1.9; 8.0); p = 0.176]. In contrast, significantly lower EAT levels of IL-1ra were found in Group 2 compared to Group 1 [101 pg/ml (40; 577) vs. 1344 pg/ml (155; 5327); p = 0.002]. No correlation was found between EAT levels of IL-1ß and CD86 and CD64 events. CONCLUSION: The present study explores the levels of IL-1ß and IL-1ra in the serum and in EAT of CCS and ACS patients. ACS seems to be associated to a loss of the counter-regulatory activity of IL-1ra against the pro-inflammatory effects related to IL-1ß activation.

Echocardiographic Epicardial Adipose Tissue Thickness for Risk Stratification of Patients With Heart Failure.

BACKGROUND AND AIMS: Epicardial adipose tissue (EAT) has been shown to be involved in the pathogenesis and progression of heart failure (HF). In this study we aimed to explore the predictive value of echocardiographic EAT thickness on prognosis of a selected population of HF patients. METHODS: The patient population included n. 69 consecutive patients with systolic HF referred to implantable cardioverter defibrillator (ICD) implantation for primary or secondary prevention. At the time of enrolment, echocardiographic EAT thickness was assessed in all patients along with demographic and clinical data. The study had a median follow-up time of 49.8 months. We assessed the prognostic predictive value of EAT thickness on a composite clinical and arrhythmic outcome including HF related deaths, new hospital admissions for HF worsening, and atrial and life threatening ventricular arrhythmic events. Clinical and arrhythmic outcomes were also evaluated separately. RESULTS: At univariate analysis, EAT thickness significantly predicted all the three outcomes considered. Of interest, at multivariate analysis, after adjusting for known risk factor, EAT remained significantly associated to the composite [HR 1.18 (1.09-1.28); p < 0.001], arrhythmic [HR 1.14 (1.03-1.25); p = 0.008], and clinical [HR 1.14 (1.03-1.27); p = 0.010] outcomes. CONCLUSION: Echocardiographic assessment of EAT can predict outcome of HF patients and it is significantly associated with both arrhythmic and clinical events. These preliminary findings pave the way for future and larger studies aimed to definitively recognize the prognostic value of this novel risk marker in HF.

Validation of the echocardiographic assessment of epicardial adipose tissue thickness at the Rindfleisch fold for the prediction of coronary artery disease.

BACKGROUND AND AIM: Echocardiography is a promising technique for the assessment of epicardial adipose tissue (EAT). Increased EAT thickness is associated with different cardiac diseases, including; coronary artery disease (CAD). Since several different echocardiographic approaches have been proposed to measure EAT, the identification of a standardized method is needed. We propose the assessment of EAT maximal thickness at the Rindfleisch fold, the reproducibility of this measurement and its correlation with EAT thickness and volume assessed at cardiac magnetic resonance (CMR). Finally, we will test the predictive role of this measurement on the presence of significant CAD. METHODS AND RESULTS: In 1061 patients undergoing echocardiography, EAT thickness was measured at the level of the Rindfleisch fold. In 70 patients, we tested the relationship between echo-EAT thickness and EAT thickness and volume assessed at CMR. In 499 patients with suspected CAD, undergoing coronary artery angiography, we tested the predictive value of EAT on the presence of significant CAD. Echo-EAT thickness measurements had an excellent reliability as indicated by the inter-observer (ICC:0.97; 95% C.I. 0.96 to 0.98) and intra-observer (ICC:0.99; 95% C.I. 0.98 to 0.99) reliability rates. Echo-EAT thickness significantly correlated with CMR-EAT thickness and volume (p < 0.001). An EAT thickness value >10 mm discriminated patients with significant CAD at coronary angiography (p < 0.001). At multivariable analysis, including demographic data and cardiovascular risk factors, EAT thickness was an independent predictor of significant CAD and showed an additive predictive value over common atherosclerotic risk factors. CONCLUSIONS: Echocardiographic assessment of EAT thickness at the level of the Rindfleisch fold represents a simple and trustworthy method. An increased EAT thickness shows an additive predictive value on CAD over common atherosclerotic risk factors, thus suggesting its potential clinical use for CAD risk stratification.

Statin therapy modulates thickness and inflammatory profile of human epicardial adipose tissue.

BACKGROUND: Epicardial adipose tissue (EAT) thickness and pro-inflammatory status has been shown to be associated with several cardiac diseases, including aortic stenosis (AS). Thus, cardiac visceral fat could represent a potential new target for drugs. In the present study we evaluate the effect of statin therapy on EAT accumulation and inflammation. METHODS: Echocardiographic EAT thickness was assessed in 193 AS patients taking (n.87) and not taking (n.106) statins, undergoing cardiac surgery. To explore the association between statin therapy and EAT inflammation, EAT biopsies were obtained for cytokines immunoassay determination in EAT secretomes. An in vitro study was also conducted and the modulation of EAT and subcutaneous adipose tissue (SCAT) secretomes by atorvastatin was assessed in paired biopsies. RESULTS: Statin therapy was significantly associated with lower EAT thickness (p < 0.0001) and with lower levels of EAT-secreted inflammatory mediators (p < 0.0001). Of note, there was a significant correlation between EAT thickness and its pro-inflammatory status. In vitro, atorvastatin showed a direct anti-inflammatory effect on EAT which was significantly higher compared to the SCAT response to statin incubation (p < 0.0001). CONCLUSIONS: The present study indicates a robust association between statin therapy and reduced EAT accumulation in patients with AS. The present data also suggest a direct relationship between EAT thickness and its inflammatory status, both modulated by statin therapy. The in vitro results support the hypothesis of a direct action of statins on EAT secretory profile. Overall our data suggest EAT as a potential new therapeutic target for statin therapy.

Long-Term Caloric Restriction Improves Cardiac Function, Remodeling, Adrenergic Responsiveness, and Sympathetic Innervation in a Model of Postischemic Heart Failure.

BACKGROUND: Caloric restriction (CR) has been described to have cardioprotective effects and improve functional outcomes in animal models and humans. Chronic ischemic heart failure (HF) is associated with reduced cardiac sympathetic innervation, dysfunctional ß-adrenergic receptor signaling, and decreased cardiac inotropic reserve. We tested the effects of a long-term CR diet, started late after myocardial infarction on cardiac function, sympathetic innervation, and ß-adrenergic receptor responsiveness in a rat model of postischemic HF. METHODS AND RESULTS: Adult male rats were randomly assigned to myocardial infarction or sham operation and 4 weeks later were further randomized to a 1-year CR or normal diet. One year of CR resulted in a significant reduction in body weight, heart weight, and heart weight/tibia length ratio when compared with normal diet in HF groups. At the end of the study period, echocardiography and histology revealed that HF animals under the CR diet had ameliorated left ventricular remodeling compared with HF rats fed with normal diet. Invasive hemodynamic showed a significant improvement of cardiac inotropic reserve in CR HF rats compared with HF-normal diet animals. Importantly, CR dietary regimen was associated with a significant increase of cardiac sympathetic innervation and with normalized cardiac ß-adrenergic receptor levels in HF rats when compared with HF rats on the standard diet. CONCLUSIONS: We demonstrate, for the first time, that chronic CR, when started after HF established, can ameliorate cardiac dysfunction and improve inotropic reserve. At the molecular level, we find that chronic CR diet significantly improves sympathetic cardiac innervation and ß-adrenergic receptor levels in failing myocardium.

Antidiabetic Drugs in Alzheimer's Disease: Mechanisms of Action and Future Perspectives.

Diabetes mellitus (DM) and Alzheimer's disease (AD) are two highly prevalent conditions in the elderly population and major public health burden. In the past decades, a pathophysiological link between DM and AD has emerged and central nervous system insulin resistance might play a significant role as a common mechanism; however, other factors such as inflammation and oxidative stress seem to contribute to the shared pathophysiological link. Both preclinical and clinical studies have evaluated the possible neuroprotective mechanisms of different classes of antidiabetic medications in AD, with some promising results. Here, we review the evidence on the mechanisms of action of antidiabetic drugs and their potential use in AD.

Impact of aging on cardiac sympathetic innervation measured by 123I-mIBG imaging in patients with systolic heart failure.

PURPOSE: Sympathetic nervous system (SNS) hyperactivity is a salient characteristic of chronic heart failure (HF) and contributes to the progression of the disease. Iodine-123 meta-iodobenzylguanidine (123I-mIBG) imaging has been successfully used to assess cardiac SNS activity in HF patients and to predict prognosis. Importantly, SNS hyperactivity characterizes also physiological ageing, and there is conflicting evidence on cardiac 123I-mIBG uptake in healthy elderly subjects compared to adults. However, little data are available on the impact of ageing on cardiac sympathetic nerve activity assessed by 123I-mIBG scintigraphy, in patients with HF. METHODS AND RESULTS: We studied 180 HF patients (age = 66.1 ± 10.5 years [yrs]), left ventricular ejection fraction (LVEF = 30.6 ± 6.3 %) undergoing cardiac 123I-mIBG imaging. Early and late heart to mediastinum (H/M) ratios and washout rate were calculated in all patients. Demographic, clinical, and echocardiographic data were also collected. Our study population consisted of 53 patients aged >75 years (age = 77.7 ± 4.0 year), 67 patients aged 62-72 years (age = 67.9 ± 3.2 years) and 60 patients aged ≤61 year (age = 53.9 ± 5.6 years). In elderly patients, both early and late H/M ratios were significantly lower compared to younger patients (p < 0.05). By multivariate analysis, H/M ratios (both early and late) and washout rate were significantly correlated with LVEF and age. CONCLUSIONS: Our data indicate that, in a population of HF patients, there is an independent age-related effect on cardiac SNS innervation assessed by 123I-mIBG imaging. This finding suggests that cardiac 123I-mIBG uptake in patients with HF might be affected by patient age.

Increased Epicardial Adipose Tissue Volume Correlates With Cardiac Sympathetic Denervation in Patients With Heart Failure.

RATIONALE: It has been reported that epicardial adipose tissue (EAT) may affect myocardial autonomic function. OBJECTIVE: The aim of this study was to explore the relationship between EAT and cardiac sympathetic nerve activity in patients with heart failure. METHODS AND RESULTS: In 110 patients with systolic heart failure, we evaluated the correlation between echocardiographic EAT thickness and cardiac adrenergic nerve activity assessed by (123)I-metaiodobenzylguanidine ((123)I-MIBG). The predictive value of EAT thickness on cardiac sympathetic denervation ((123)I-MIBG early and late heart:mediastinum ratio and single-photon emission computed tomography total defect score) was tested in a multivariate analysis. Furthermore, catecholamine levels, catecholamine biosynthetic enzymes, and sympathetic nerve fibers were measured in EAT and subcutaneous adipose tissue biopsies obtained from patients with heart failure who underwent cardiac surgery. EAT thickness correlated with (123)I-MIBG early and late heart:mediastinum ratio and single-photon emission computed tomography total defect score, but not with left ventricular ejection fraction. Moreover, EAT resulted as an independent predictor of (123)I-MIBG early and late heart:mediastinum ratio and single-photon emission computed tomography total defect score and showed a significant additive predictive value on (123)I-MIBG planar and single-photon emission computed tomography results over demographic and clinical data. Although no differences were found in sympathetic innervation between EAT and subcutaneous adipose tissue, EAT showed an enhanced adrenergic activity demonstrated by the increased catecholamine levels and expression of catecholamine biosynthetic enzymes. CONCLUSIONS: This study provides the first evidence of a direct correlation between increased EAT thickness and cardiac sympathetic denervation in heart failure.

Impact of diabetes mellitus on lymphocyte GRK2 protein levels in patients with heart failure.

BACKGROUND: Diabetes mellitus (DM) is associated with impaired prognosis in patients with heart failure (HF), but pathogenic mechanisms are unclear. In the failing heart, elevated ß-adrenergic receptor (ß-AR) activation by catecholamines causes G-protein-coupled receptor kinase-2 (GRK2) upregulation which is responsible for ß-AR signalling dysfunction. Importantly, GRK2 expression, measured in peripheral lymphocytes of HF patients, correlates with levels of this kinase in the failing myocardium reflecting the loss of hemodynamic function. Moreover, HF-related GRK2 protein overexpression promotes insulin resistance by interfering with insulin signalling. The aim of this study was to assess lymphocyte GRK2 protein levels in HF patients with and without DM. METHODS AND MATERIALS: Patients with a diagnosis of HF were enrolled in the study. All subjects underwent a complete clinical examination (including NYHA functional class assessment and echocardiography) and blood draw for serum N-terminal pro-brain natriuretic peptide (NT-proBNP), lymphocyte GRK2 and plasma norepinephrine (NE) levels. Demographic data including age, sex, medications, cardiovascular risk factors and presence of comorbidities were also collected. RESULTS: Two hundred and sixty-eight patients with HF (left ventricular ejection fraction [LVEF] 30.6 ± 7.6%) with and without DM were enrolled. No differences between the two groups were found in terms of demography, HF aetiology, LVEF, NYHA class, NE and NT-proBNP. GRK2 was significantly higher in patients with DM compared to non-DM. At multivariate linear regression analysis, LVEF, NE, NT-proBNP and diabetes came out to be independent predictors of GRK2 levels in the overall study population. CONCLUSION: In HF patients, DM is associated with significantly more elevated lymphocyte GRK2 protein levels, likely reflecting more compromised cardiac ß-AR signalling/function, despite similar hemodynamic status and neuro-hormonal activation compared to patients without DM. These findings contribute to explain the negative prognostic impact of DM in patients with HF.