Cholinergic activity regulates the secretome of epicardial adipose tissue: Association with atrial fibrillation.

Botulinum toxin injection on epicardial fat, which inhibits acetylcholine (ACh) release, reduced the presence of atrial fibrillation (AF) in patients after heart surgery. Thus, we wanted to study the profile of the released proteins of epicardial adipose tissue (EAT) under cholinergic activity (ACh treatment) and their value as AF predictors. Biopsies, explants, or primary cultures were obtained from the EAT of 85 patients that underwent open heart surgery. The quantification of muscarinic receptors (mAChR) by real-time polymerase chain reaction or western blot showed their expression in EAT. Moreover, mAChR Type 3 was upregulated after adipogenesis induction (p < 0.05). Cholinergic fibers in EAT were detected by vesicular ACh transporter levels and/or acetylcholinesterase activity. ACh treatment modified the released proteins by EAT, which were identified by nano-high-performance liquid chromatography and TripleTOF analysis. These differentially released proteins were involved in cell structure, inflammation, or detoxification. After testing the plasma levels of alpha-defensin 3 (inflammation-involved protein) of patients who underwent open heart surgery ( n = 24), we observed differential levels between the patients who developed or did not develop postsurgery AF (1.58 ± 1.61 ng/ml vs. 6.2 ± 5.6 ng/ml; p < 0.005). The cholinergic activity on EAT might suggest a new mechanism for studying the interplay among EAT, autonomic nervous system dysfunction, and AF.

Prognostic value of nutrition status in the response of cardiac resynchronization therapy.

BACKGROUND: Cardiac resynchronization therapy (CRT) is indicated in symptomatic heart failure (HF) patients after achieving optimal medical therapy. However, there are still a large percentage of patients who do not respond to CRT. Malnutrition is a frequent comorbidity in patients with HF, and it is associated with a poorer prognosis. Here, we evaluate the nutritional status of patients assessed by Controlling Nutritional Status (CONUT) score and its association with structural remodeling and cardiovascular events. METHODS: We investigated the effect of CONUT on HF/death in 302 consecutive patients with a CRT device implanted between 2005 and 2015 in a single tertiary center. We categorized the patients into three groups: normal nutritional status (CONUT 0-1), mild malnutrition (CONUT 2-4) and moderate-severe malnutrition (CONUT ≥ 5). Changes in nutritional status were assessed in patients with mild-to-severe malnutrition prior to CRT. RESULTS: One hundred and forty-eight patients exhibited normal nutritional status (49.0%), 99 patients exhibited mild malnutrition (32.8%) and 55 patients exhibited moderate-severe malnutrition (18.2%). CONUT scores of at least 2 were associated with higher risk of HF/death compared with CONUT 0-1. Significant left ventricular (LV) reverse remodeling was noted in patients with better nutritional status. In addition, those malnutrition patients at baseline that improved nutritional state exhibited fewer HF/death events at follow-up. CONCLUSION: CONUT score prior to CRT was an independent risk factor of death/HF and was correlated with LV reverse remodeling. Improvements in CONUT score during long-term follow-up were associated with a reduction in the rate of HF/death.

A New Biomarker Tool for Risk Stratification in "de novo" Acute Heart Failure (OROME).

Background: Inflammation is one of the mechanisms involved in heart failure (HF) pathophysiology. Thus, the acute phase reactant protein, orosomucoid, was associated with a worse post-discharge prognosis in de novo acute HF (AHF). However, the presence of anti-inflammatory adipokine, omentin, might protect and reduce the severity of the disease. We wanted to evaluate the value of omentin and orosomucoid combination for stratifying the risk of these patients. Methods and Results: Two independent cohorts of patients admitted for de novo AHF in two centers were included in the study (n = 218). Orosomucoid and omentin circulating levels were determined by ELISA at discharge. Patients were followed-up for 317 (3-575) days. A predictive model was determined for the primary endpoint, death, and/or HF readmission. Differences in survival were evaluated using a Log-rank test. According to cut-off values of orosomucoid and omentin, patients were classified as UpDown (high orosomucoid and low omentin levels), equal (both proteins high or low), and DownUp (low orosomucoid and high omentin levels). The Kaplan Meier determined a worse prognosis for the UpDown group (Long-rank test p = 0.02). The predictive model that includes the combination of orosomucoid and omentin groups (OROME) + NT-proBNP values achieved a higher C-index = 0.84 than the predictive model with NT-proBNP (C-index = 0.80) or OROME (C-index = 0.79) or orosomucoid alone (C-index = 0.80). Conclusion: The orosomucoid and omentin determination stratifies de novo AHF patients into the high, mild, and low risk of rehospitalization and/or death for HF. Its combination with NT-proBNP improves its predictive value in this group of patients.

CD5L, Macrophage Apoptosis Inhibitor, Was Identified in Epicardial Fat-Secretome and Regulated by Isoproterenol From Patients With Heart Failure.

OBJECTIVES: Neurohormonal dysfunction, which can regulate epicardial fat activity, is one of the main promoters of atrial fibrillation (AF) in patients with heart failure (HF). Our aim was to study the epicardial fat mediators for AF in patients with HF and its catecholaminergic regulation. METHODS: We have included 29 patients with HF who underwent cardiac surgery and were followed up for 5 years. Released proteins by epicardial adipose tissue (EAT) after isoproterenol treatment were identified by nano-high-performance liquid chromatography (HPLC) and triple time-of-flight (TOF) analysis. Common and differential identified proteins in groups of patients with AF before and after surgery were determined by the FunRich tool. Plasma and epicardial fat biopsy proteins were quantified by western blot. RESULTS: Our results identified 17 common released proteins by EAT, after isoproterenol treatment, from HF patients who suffered AF or developed new-onset AF during follow-up. Mostly, they were involved on inflammatory response and extracellular matrix. One of them was CD5L, a macrophage apoptosis inhibitor. Its secretion by isoproterenol treatment was validated on western blot. The CD5L levels on epicardial fat were also higher in the group of male patients who present or develop AF (0.44 ± 0.05 vs. 0.18 ± 0.15; p < 0.016). However, there were no differences regarding plasma levels. CONCLUSION: Our results suggest the role of epicardial fat CD5L as a mediator of AF and its possible paracrine effect by catecholaminergic activity.

Long-Term Weight Gain Associated With High Omentin Levels at Hospital Discharge Improves Prognosis of Patients Following Acute Heart Failure.

A obesity paradox has been described following heart failure (HF). The aim of this study was to analyze the association between food intake-involved adipokines and long-term weight changes. Leptin, adiponectin, and omentin were analyzed in 92 acute HF (AHF) patients at discharge, classified on the basis of weight gains or losses > 6%. The mean follow-up was 256 ± 143 days. Leptin and adiponectin levels were similar among weight groups. However, omentin levels were higher in those patients who had gained weight (16 ± 5 ng/mL) than in those who had lost weight (12 ± 4 ng/mL) or showed no weight change (11 ± 5 ng/mL; p < 0.002). Omentin levels were the best independent predictors for patients with weight gain, who had less mortality and hospital readmission during the follow-up. The association between omentin levels and weight gain might explain part of the obesity paradox in HF.

Cardiac resynchronization therapy outcomes in patients under nonoptimal medical therapy.

BACKGROUND: Cardiac resynchronization therapy (CRT) is indicated in symptomatic heart failure (HF) patients after achieving optimal medical therapy (OMT). However, many patients may not be under OMT when the CRT device is implanted. Here, we evaluate the long-term benefits of CRT in symptomatic HF patients receiving or not OMT. METHODS: We investigated the effect of OMT on HF developing or death in 328 consecutive patients with a CRT device implanted between 2005 and 2015 in a single tertiary center. After the CRT implant, we categorized the patients into three groups: no OMT, OMT at baseline and after 1 year of follow-up, and OMT only at the 1-year follow-up but not at baseline. We used multivariate Cox proportional hazards model to determine the effect of OMT on clinical outcomes. RESULTS: One hundred and twenty-two patients (37.2%) received OMT prior to CRT. OMT at baseline was not associated with a reduced risk of death or HF (HR 0.72; 95% CI 0.50-1.02; P = 0.067) compared with no-basal-OMT patients. After CRT, patients without OMT had a higher risk of death or HF than patients who received OMT in follow-up (HR 1.72, 95% CI 1.07-2.78, P = 0.025), and the risk of the patients who received OMT at baseline and at the 1-year follow-up was similar to that of the patients who achieved OMT at the 1-year follow-up (HR 0.90, 95% CI 0.54-1.50, P = 0.682). CONCLUSION: Basal OMT prior to CRT is not associated with better outcomes in terms of HF/death compared with no basal OMT. The subgroup of patients who achieved OMT at the 1-year follow-up exhibited a reduced risk of HF and death compared with patients who did not.