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SCOPE: Perinatal nutritional disturbances may "program" an increased cardio-metabolic risk in adulthood; however, few experimental studies have explored their effects on mature and/or old animal. This study aims to investigate the influence of postnatal overfeeding (PNOF) on cardiac function, sensitivity to ischemia-reperfusion (I-R) injury in vivo, glucose metabolism, and metabolic profile of pericardial adipose tissue (PAT) in young (4 months), adult (6 months), old (12 months), and very old (18 months) male mice. METHODS AND RESULTS: Two days after birth, PNOF is induced by adjusting the litter size of C57BL/6 male mice to three pups/mother, while the normally fed (NF) control group is normalized to nine pups/mother. After weaning, all mice have free access to standard diet. Glucose/insulin tests and in vivo myocardial I-R injury are conducted on mice aged from 2 to 12 months, while echocardiography is performed at all ages up to 18 months. PNOF mice exhibit an early and persistent 10-20% increase in body weight and a 10% decrease in left ventricular ejection fraction throughout their lifespan. In PNOF mice aged 4, 6, and 12 months, glucose intolerance and insulin resistance are observed, as well as a 27-34% increase in infarct size. This is accompanied by a higher PAT mass with increased inflammatory status. CONCLUSION: Short-term PNOF results in nutritional programming, inducing long-lasting alterations in glucose metabolism and cardiac vulnerability in male mice, lasting up to 12 months.
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Camundongos Endogâmicos C57BL , Infarto do Miocárdio , Animais , Masculino , Resistência à Insulina , Síndrome Metabólica/etiologia , Hipernutrição/complicações , Hipernutrição/fisiopatologia , Camundongos , HiperfagiaRESUMO
This review examines the impact of obesity on the pathophysiology of heart failure with preserved ejection fraction (HFpEF) and focuses on novel mechanisms for HFpEF prevention using a glucagon-like peptide-1 receptor agonism (GLP-1 RA). Obesity can lead to HFpEF through various mechanisms, including low-grade systemic inflammation, adipocyte dysfunction, accumulation of visceral adipose tissue, and increased pericardial/epicardial adipose tissue (contributing to an increase in myocardial fat content and interstitial fibrosis). Glucagon-like peptide 1 (GLP-1) is an incretin hormone that is released from the enteroendocrine L-cells in the gut. GLP-1 reduces blood glucose levels by stimulating insulin synthesis, suppressing islet α-cell function, and promoting the proliferation and differentiation of ß-cells. GLP-1 regulates gastric emptying and appetite, and GLP-1 RA is currently indicated for treating type 2 diabetes (T2D), obesity, and metabolic syndrome (MS). Recent evidence indicates that GLP-1 RA may play a significant role in preventing HFpEF in patients with obesity, MS, or obese T2D. This effect may be due to activating cardioprotective mechanisms (the endogenous counter-regulatory renin angiotensin system and the AMPK/mTOR pathway) and by inhibiting deleterious remodeling mechanisms (the PKA/RhoA/ROCK pathway, aldosterone levels, and microinflammation). However, there is still a need for further research to validate the impact of these mechanisms on humans.
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Diabetes Mellitus Tipo 2 , Receptor do Peptídeo Semelhante ao Glucagon 1 , Insuficiência Cardíaca , Síndrome Metabólica , Volume Sistólico , Humanos , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/complicações , Síndrome Metabólica/metabolismo , Síndrome Metabólica/tratamento farmacológico , Volume Sistólico/efeitos dos fármacos , Animais , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Obesidade/metabolismo , Obesidade/complicações , Obesidade/tratamento farmacológicoRESUMO
Accumulation of ectopic pericardial adipose tissue has been associated with cardiovascular complications which, in part, may relate to adipose-derived factors that regulate vascular responses and angiogenesis. We sought to characterize adipose tissue microvascular angiogenic capacity in subjects who underwent elective cardiac surgeries including aortic, valvular, and coronary artery bypass grafting. Pericardial adipose tissue was collected intraoperatively and examined for angiogenic capacity. Capillary sprouting was significantly blunted (twofold, p <0.001) in subjects with coronary artery disease (CAD) (age 60 ± 9 years, body mass index [BMI] 32 ± 4 kg/m2, low-density lipoprotein cholesterol [LDL-C] 95 ± 46 mg/100 ml, n = 29) compared with age-, BMI-, and LDL-C matched subjects without angiographic obstructive CAD (age 59 ± 10 y, BMI 35 ± 9 kg/m2, LDL-C 101 ± 40 mg/100 ml, n = 12). For potential mechanistic insight, we performed mRNA expression analyses using quantitative real-time polymerase chain reaction and observed no significant differences in pericardial fat gene expression of proangiogenic mediators vascular endothelial growth factor-A (VEGF-A), fibroblast growth factor-2 (FGF-2), and angiopoietin-1 (angpt1), or anti-angiogenic factors soluble fms-like tyrosine kinase-1 (sFlt-1) and endostatin. In contrast, mRNA expression of anti-angiogenic thrombospondin-1 (TSP-1) was significantly upregulated (twofold, p = 0.008) in CAD compared with non-CAD subjects, which was confirmed by protein western-immunoblot analysis. TSP-1 gene knockdown using short hairpin RNA lentiviral delivery significantly improved angiogenic deficiency in CAD (p <0.05). In conclusion, pericardial fat in subjects with CAD may be associated with an antiangiogenic profile linked to functional defects in vascularization capacity. Local paracrine actions of TSP-1 in adipose depots surrounding the heart may play a role in mechanisms of ischemic heart disease.
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Doença da Artéria Coronariana , Isquemia Miocárdica , Humanos , Pessoa de Meia-Idade , Idoso , Fator A de Crescimento do Endotélio Vascular/metabolismo , Trombospondina 1/genética , Trombospondina 1/metabolismo , LDL-Colesterol/metabolismo , Isquemia Miocárdica/complicações , Tecido Adiposo , Doença da Artéria Coronariana/etiologia , RNA Mensageiro/metabolismoRESUMO
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is the most common idiopathic interstitial lung disease. Clinical models to accurately evaluate the prognosis of IPF are currently lacking. This study aimed to construct an easy-to-use and robust prediction model for transplant-free survival (TFS) of IPF based on clinical and radiological information. METHODS: A multicenter prognostic study was conducted involving 166 IPF patients who were followed up for 3 years. The end point of follow-up was death or lung transplantation. Clinical information, lung function tests, and chest computed tomography (CT) scans were collected. Body composition quantification on CT was performed using 3D Slicer software. Risk factors in blood routine examination-radiology-pulmonary function (BRP) were identified by Cox regression and utilized to construct the "BRP Prognosis Model". The performance of the BRP model and the gender-age-physiology variables (GAP) model was compared using time-ROC curves, calibration curves, and decision curve analysis (DCA). Furthermore, histopathology fibrosis scores in clinical specimens were compared between the different risk stratifications identified by the BRP model. The correlations among body composition, lung function, serum inflammatory factors, and profibrotic factors were analyzed. RESULTS: Neutrophil percentage > 68.3%, pericardial adipose tissue (PAT) > 94.91 cm3, pectoralis muscle radiodensity (PMD) ≤ 36.24 HU, diffusing capacity of the lung for carbon monoxide/alveolar ventilation (DLCO/VA) ≤ 56.03%, and maximum vital capacity (VCmax) < 90.5% were identified as independent risk factors for poor TFS among patients with IPF. We constructed a BRP model, which showed superior accuracy, discrimination, and clinical practicability to the GAP model. Median TFS differed significantly among patients at different risk levels identified by the BRP model (low risk: TFS > 3 years; intermediate risk: TFS = 2-3 years; high risk: TFS ≈ 1 year). Patients with a high-risk stratification according to the BRP model had a higher fibrosis score on histopathology. Additionally, serum proinflammatory markers were positively correlated with visceral fat volume and infiltration. CONCLUSIONS: In this study, the BRP prognostic model of IPF was successfully constructed and validated. Compared with the commonly used GAP model, the BRP model had better performance and generalization with easily obtainable indicators. The BRP model is suitable for clinical promotion.
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Fibrose Pulmonar Idiopática , Humanos , Fibrose Pulmonar Idiopática/diagnóstico por imagem , Fibrose Pulmonar Idiopática/patologia , Pulmão/patologia , Prognóstico , Capacidade Vital , Biomarcadores , Fibrose , Estudos RetrospectivosRESUMO
Epicardial adipose tissue (EAT) has been associated with the development of many cardiovascular abnormalities, of which the development of atrial fibrillation (AFIB) in this group of patients is not an uncommon finding. Several mechanisms have been proposed to explain the role of EAT in the development of AFIB. It involves cardiac remodeling owing to the underlying fatty infiltration and the subsequent inflammation and fibrosis. This leads to the formation of ectopic foci that can lead to AFIB. Some studies propose that structural and valvular heart disease and increased hemodynamic stress further augment the development of AFIB in patients with underlying EAT. The degree of development of AFIB is also related to EAT thickness and volume. Therefore, EAT quantification can be used as an imaging technique to predict cardiovascular outcomes in these patients. Obesity also plays an important role in the development of AFIB both as an independent factor and by leading to adipose tissue deposition on the epicardial tissue. Understanding the pathophysiology of EAT is important as it can lead to the development of therapies that can target obesity as a risk factor for preventing AFIB. Some promising therapies have already been investigated for decreasing the risk of AFIB in patients with EAT. Dietary changes and weight loss have been shown to reduce the deposition of fat on epicardial tissue. Antidiabetic drugs and statin therapy have also shown promising results. Bariatric surgery has been shown to decrease EAT volume on echocardiography in obese patients.
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BACKGROUND Pericardial adipose tissue (PAT) is the visceral adipose tissue compartment surrounding the heart. Experimental and observational research has suggested that greater PAT deposition might mediate cardiovascular disease, independent of general or subcutaneous adiposity. We characterize the genetic architecture of adiposity-adjusted PAT and identify causal associations between PAT and adverse cardiac magnetic resonance imaging measures of cardiac structure and function in 28 161 UK Biobank participants. METHODS AND RESULTS The PAT phenotype was extracted from cardiac magnetic resonance images using an automated image analysis tool previously developed and validated in this cohort. A genome-wide association study was performed with PAT area set as the phenotype, adjusting for age, sex, and other measures of obesity. Functional mapping and Bayesian colocalization were used to understand the biologic role of identified variants. Mendelian randomization analysis was used to examine potential causal links between genetically determined PAT and cardiac magnetic resonance-derived measures of left ventricular structure and function. We discovered 12 genome-wide significant variants, with 2 independent sentinel variants (rs6428792, P=4.20×10-9 and rs11992444, P=1.30×10-12) at 2 distinct genomic loci, that were mapped to 3 potentially causal genes: T-box transcription factor 15 (TBX15), tryptophanyl tRNA synthetase 2, mitochondrial (WARS2) and early B-cell factor-2 (EBF2) through functional annotation. Bayesian colocalization additionally suggested a role of RP4-712E4.1. Genetically predicted differences in adiposity-adjusted PAT were causally associated with adverse left ventricular remodeling. CONCLUSIONS This study provides insights into the genetic architecture determining differential PAT deposition, identifies causal links with left structural and functional parameters, and provides novel data about the pathophysiological importance of adiposity distribution.
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Bancos de Espécimes Biológicos , Estudo de Associação Genômica Ampla , Humanos , Teorema de Bayes , Pericárdio , Obesidade , Tecido Adiposo , Reino Unido , Gordura Intra-Abdominal , Proteínas com Domínio TRESUMO
OBJECTIVES: Excess pericardial adipose tissue (PAT) is associated with a higher risk of cardiovascular diseases. Currently, available methods for reducing PAT volume include weight loss through diet and exercise, weight loss with medications, and bariatric surgery. However, these methods are all limited by low patient compliance to maintain the results. We have developed an injectable ice slurry that could selectively target and reduce subcutaneous adipose tissue volume. The aim of this study was to investigate the feasibility and safety of using injectable slurry to selectively reduce PAT volume in a preclinical large animal model. METHODS: PAT in Yucatan swine was injected with slurry or room temperature control solution. All animals were imaged with baseline chest computed tomography (CT) before slurry injection and at 2 months after injection to quantify PAT volume. Specimens from injected and noninjected PAT were harvested for histology. RESULTS: Slurry treatment of PAT was well tolerated in all animals. Slurry-induced selective cryolipolysis in treated PAT. CT imaging showed decrease in PAT volume in treated area at 8 weeks posttreatment compared to baseline, that was significantly different from control solution treated group (median [range]: -29.66 [-35.07 to -27.92]% vs. -1.50 [-11.69 to 8.69]% in control animals respectively, p < 0.05). CONCLUSIONS: This study demonstrated that slurry injection into PAT is feasible in a large animal model. Slurry injection was safe and effective in inducing selective cryolipolysis in PAT and reducing PAT volume. Slurry reduction of PAT could potentially serve as a novel treatment for cardiovascular diseases.
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Doenças Cardiovasculares , Gelo , Suínos , Animais , Tecido Adiposo/patologia , Gordura Subcutânea , Redução de PesoRESUMO
BACKGROUND: Pericardial adipose tissue volume (PAT) and coronary artery calcification (CAC) are prognostic indicators for future cardiovascular events; however, no studies have assessed the long-term associations of adherence to dietary patterns (DPs) with PAT and CAC in adults with and without type 1 diabetes (T1D). OBJECTIVES: We investigated the longitudinal associations of the Mediterranean Diet (MedDiet) and Dietary Approaches to Stop Hypertension (DASH) diet with PAT and CAC progression in adults with and without T1D. METHODS: The Coronary Artery Calcification in Type 1 Diabetes (CACTI) study is a population-based, prospective study of 652 T1D and 764 nondiabetic mellitus (nonDM) (19-56 y) participants that began in 2000-2002 with follow-up visits in 2003-2004 and 2006-2007. At each visit, food frequency questionnaires were collected and used to develop adherence scores for the MedDiet and DASH diets. PAT and CAC were measured at each visit using electron beam computed tomography. CAC progression was defined as a ≥2.5 mm square root-transformed volume. Mixed effect models were used to conduct statistical analyses. RESULTS: Combined models found a significant-0.09 cm3 (95% CI: -0.14, -0.03; P = 0.0027) inverse association in PAT for every 1-point increase in the MedDiet score and a significant-0.26 cm3 (95% CI: -0.38, -0.14; P < 0.0001) inverse association in PAT for every 1-point increase in the DASH score. In combined models, the DPs were not significantly associated with lower odds of CAC progression; however, both DPs had significant interactions by diabetes status for CAC. Only the DASH diet was associated with lower odds of CAC progression in the nonDM group (OR: 0.96; 95% CI: 0.93, 0.99; P = 0.0224). CONCLUSIONS: These data suggest that the DPs are associated with lower PAT, which may reduce future cardiovascular events. The DASH diet may be beneficial for lower odds of CAC progression in those without T1D.
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Doença da Artéria Coronariana , Diabetes Mellitus Tipo 1 , Dieta Mediterrânea , Calcificação Vascular , Adulto , Humanos , Estados Unidos , Diabetes Mellitus Tipo 1/complicações , Adiposidade , Estudos Prospectivos , Calcificação Vascular/complicações , Obesidade/complicações , Fatores de Risco , Progressão da DoençaRESUMO
AIM: To determine the frequency, distribution and characteristics of ectopic obesity in patients without manifested cardiovascular disease. MATERIALS AND METHODS: We examined 320 patients without manifested cardiovascular disease (average age 63.813.9 years), 38 of them without cardiovascular risk factors (healthy referent group). Anthropometric indicators were measured, body mass index (BMI) was calculated. Degree, type of obesity, lipid profile were evaluated. All patients underwent multi-detector chest computed tomography in spiral mode on Toshiba Aquilion Prime scanner using standardized protocol. Perivascular adipose tissue (PVAT) and pericardial adipose tissue (PAT) were detected using specialized semi-automatic software Tissue Composition Module QCTPro (Mindways Software, Inc., USA) after scanner calibration with special phantom. PAT and PVAT exceeding the 90th percentile in the healthy referent group were considered as ectopic obesity. Statistical analysis was performed using Statistica 10.0 software (StatSoft Inc., USA). RESULTS: PAT volume 3.2 cm3 and PVAT volume 0.4 cm3 were criteria for high pericardial and high perivascular fat; 81 (25.2%) patients had ectopic obesity, 85 (26.5%) patients abdominal obesity; 146 (42.9%) people had high pericardial fat, 134 (39.4%) high perivascular fat. The frequency of ectopic obesity in patients with arterial hypertension (AH) was statistically significantly higher compared to persons without AH. Significantly more often ectopic forms of obesity were detected in patients with overweight and obesity. The high pericardial fat and high perivascular fat were found in patients with overweight and normal body weight. When comparing the clinical characteristics of patients with abdominal and ectopic obesity, metabolic parameters, as well as the incidence of hypertension and dyslipidemia, did not differ significantly. CONCLUSION: Ectopic obesity can develop outside of global obesity. In addition, this type of obesity is accompanied by metabolic disorders and AH, regardless of the abdominal distribution of adipose tissue.
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Doenças Cardiovasculares , Hipertensão , Humanos , Pessoa de Meia-Idade , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Sobrepeso , Obesidade/complicações , Obesidade/diagnóstico , Obesidade/epidemiologia , Tecido Adiposo/diagnóstico por imagem , Hipertensão/diagnóstico , Hipertensão/epidemiologia , Hipertensão/complicações , LipídeosRESUMO
As a vital adipokine, Adipsin is closely associated with cardiovascular risks. Nevertheless, its role in the onset and development of cardiovascular diseases remains elusive. This study was designed to examine the effect of Adipsin on survival, cardiac dysfunction and adverse remodeling in the face of myocardial infarction (MI) injury. In vitro experiments were conducted to evaluate the effects of Adipsin on cardiomyocyte function in the face of hypoxic challenge and the mechanisms involved. Our results showed that Adipsin dramatically altered expression of proteins associated with iron metabolism and ferroptosis. In vivo results demonstrated that Adipsin upregulated levels of Ferritin Heavy Chain (FTH) while downregulating that of Transferrin Receptor (TFRC) in peri-infarct regions 1 month following MI. Adipsin also relieved post-MI-associated lipid oxidative stress as evidenced by decreased expression of COX2 and increased GPX4 level. Co-immunoprecipitation and immunofluorescence imaging prove a direct interaction between Adipsin and IRP2. As expected, cardioprotection provided by Adipsin depends on the key molecule of IRP2. These findings revealed that Adipsin could be efficiently delivered to the heart by exosomes derived from pericardial adipose tissues. In addition, Adipsin interacted with IRP2 to protect cardiomyocytes against ferroptosis and maintain iron homeostasis. Therefore, Adipsin-overexpressed exosomes derived from pericardial adipose tissues may be a promising therapeutic strategy to prevent adverse cardiac remodeling following ischemic heart injury.
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Purpose: Excessive accumulation of free fatty acids in the coronary arteries can lead to coronary artery disease (CAD). Quantification of epicardial adipose tissue (EAT) and pericardial adipose tissue (PAT) is beneficial to understand its relationship with CAD, hypertension (HT), and diabetes. Material and methods: This retrospective study included 54 patients who underwent CT coronary angiogram using a multidetector row CT scanner. The EAT and PAT volumes from cardiac images were quantified using Image J software. The severity of CAD was graded using the CAD-RADS score. Results: Twenty-nine patients had no CAD, 21 patients had significant CAD, and 4 patients had insignificant CAD. Out of 21 patients with significant CAD, 14 had involvement of multiple coronary arteries. The EAT and PAT volumes were higher in patients with HT, DM, CAD-present group and significant-CAD-present group, but this was not statistically significant except the PAT volume with respect to diabetes. Significant correlation was found between EAT volume and calcium score (p = 0.035) and between EAT volume and total cholesterol level (p = 0.017). Significant differences in the EAT volumes were found in different CAD-RADS categories in the right coronary artery (RCA). From the threshold values, it was observed that CAD can develop in LAD even at lower of EAT and PAT volumes. Conclusions: Quantification of EAT and PAT volumes is beneficial in understanding its relationship with the presence and severity of coronary artery disease and its risk factors.
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Background: Pericardial adipose tissue (PAT) has been associated with adverse cardiac events. In this study, we evaluated changes of PAT in patients with breast cancer during and after anthracycline-based chemotherapy and explored the clinical variables associated with increases in PAT volume at the completion of chemotherapy. Methods: A total of 278 breast cancer patients who were receiving anthracycline-based chemotherapy were retrospectively enrolled. Their PAT volumes were measured using non-contrast chest computed tomography (CT) images from a dedicated workstation. We compared these volumes to their measurements at baseline, during different chemotherapy cycles, at and after chemotherapy completion. We identified the clinical variables associated with increases in PAT volume at chemotherapy completion using logistic regression analyses. Results: At the completion of chemotherapy, PAT volumes were shown to have increased compared to baseline measurements (87.67±45.09 vs. 104.25±47.74 cm3; P=0.00). After 4, 6, and 8 chemotherapy cycles, PAT volumes increased from the baseline measurement by 9.48% [95% confidence interval (CI): -2.30% to 21.27%], 14.75% (95% CI: 4.68% to 24.82%), and 20.02% (95% CI: 11.38% to 28.66%), respectively. Compared to volumes measured at chemotherapy completion (104.25±47.74 cm3), PAT volumes at 6 and 12 months after chemotherapy completion were 105.23±49.27 and 107.56±46.34 cm3, respectively. The differences between chemotherapy completion and follow-up PAT volumes were not statistically significant. A variable associated with an increase in PAT from baseline to chemotherapy completion was the number of chemotherapy cycles (8 vs. 4) [odds ratio (OR) =3.850; 95% CI: 1.751 to 8.488]. Conclusions: Patients with breast cancer who undergo anthracycline-based chemotherapy can experience unfavorable PAT volume increases, which are maintained after the completion of treatment. Patients at risk of increases in PAT volume at chemotherapy completion can be identified based on clinical risk factors and targeted for interventions.
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Background and aims: Epicardial and pericardial adipose tissue (EAT and PAT) associate with atherosclerosis, however, discussed to have different inflammatory properties. We examined the NLRP3 inflammasome related pathway, playing a pivotal role in atherosclerosis, in EAT, PAT and subcutaneous AT (SAT), their relationship to cell types and anthropometric measures in patients undergoing coronary artery bypass grafting. Methods: Biopsies from EAT, PAT and SAT were collected from 52 patients with coronary heart disease (CHD) (median body weight 85.0 kg) and 22 controls. RNA was extracted and expression of interleukin (IL)-1ß, IL-18, NLRP3, Caspase-1, toll-like receptor 4 (TLR4), IL-6, IL-6 receptor and gp130 were analyzed by RT-PCR. Results: Limited differences in any genes between CHD patients and controls. IL-18 and IL-6 were 4-fold higher expressed in EAT versus PAT (p < 0.01, both) and SAT (p < 0.001, both), whereas caspase-1, IL-6R and gp130 were higher expressed in SAT compared to the other compartments (all p = 0.06-<0.001). Significant correlations between SAT and PAT gene expressions (r = 0.358-0.579, all p ≤ 0.01). Especially NLRP3 and TLR4 associated with the expression of macrophages in all compartments (all p < 0.001). In EAT IL-18 correlated inversely with the expression of macrophages and T-cells. In SAT and PAT most of the mediators associated with body weight. Conclusions: Higher expression of IL-18 and IL-6 was observed in EAT in our non-obese CHD patients, not related to inflammatory cells. The NLRP3 inflammasome activation in SAT that mirrored PAT, both related to anthropometrics, suggest that SAT samples, being easily available, to a certain degree, represent adipose tissue inflammation in general.
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BACKGROUND: Pericardial adipose tissue (PAT) is associated with adverse cardiovascular outcomes in those with and without established heart failure (HF). However, it is not known whether PAT is associated with adverse outcomes in patients with end-stage HF undergoing left ventricular assist device (LVAD) implantation. This study aimed to evaluate the associations between PAT and LVAD-associated outcomes. METHODS AND RESULTS: We retrospectively measured computed tomography-derived PAT volumes in 77 consecutive adults who had available chest CT imaging prior to HeartMate 3 LVAD surgery between October 2015 and March 2019 at Duke University Hospital. Study groups were divided into above-median (≥219 cm3) and below-median (<219 cm3) PAT volume. Those with above-median PAT had a higher proportion of atrial fibrillation, chronic kidney disease and ischemic cardiomyopathy. Groups with above-median vs below-median PAT had similar Kaplan-Meier incidence rates over 2 years for (1) composite all-cause mortality, redo-LVAD surgery and cardiac transplantation (35.9 vs 32.2%; log-rank Pâ¯=â¯0.65) and (2) composite incident hospitalizations for HF, gastrointestinal bleeding, LVAD-related infection, and stroke (61.5 vs 60.5%; log-rank Pâ¯=â¯0.67). CONCLUSIONS: In patients with end-stage HF undergoing LVAD therapy, PAT is not associated with worse 2-year LVAD-related outcomes. The significance of regional adiposity vs obesity in LVAD patients warrants further investigation.
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Insuficiência Cardíaca , Transplante de Coração , Coração Auxiliar , Tecido Adiposo/diagnóstico por imagem , Adulto , Coração Auxiliar/efeitos adversos , Humanos , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Background Pathophysiologic mechanisms underlying cardiac structural and functional changes in obesity are complex and linked to adipocytokines released from pericardial adipose tissue (PAT) and cardiomyocyte apoptosis. Although leptin is involved in various pathological conditions, its role in paracrine action of pericardial adipose tissue on myocardial apoptosis remains unknown. This study was designed to investigate the role of PAT-derived leptin on myocardial apoptosis in high-fat diet-induced obese rats. Methods and Results Hearts were isolated from lean or high-fat diet-induced obese Wistar rats for myocardial remodeling studies. Obese rats had abnormal myocardial structure, diastolic dysfunction, greatly elevated cardiac apoptosis, enhanced cardiac fibrosis, and increased oxidative stress level. ELISA detected significantly higher than circulating leptin level in PAT of obese, but not lean, rats. Western blot and immunohistochemical analyses demonstrated increased leptin receptor density in obese hearts. H9c2 cardiomyoblasts, after being exposed to PAT-conditioned medium of obese rats, exhibited pronounced reactive oxygen species-mediated apoptosis, which was partially reversed by leptin antagonist. Moreover, leptin derived from PAT of obese rats inhibited Na+/K+-ATPase activity of H9c2 cells through stimulating reactive oxygen species, thereby activating calcium-dependent apoptosis. Pretreatment with specific inhibitors revealed that Janus kinase 2/signal transducer and activator of transcription 3 and phosphoinositide 3-kinase/protein kinase B signaling pathways were involved in leptin-induced myocardial apoptosis. Conclusions PAT-derived leptin induces myocardial apoptosis in high-fat diet-induced obese rats via activating Janus kinase 2/signal transducer and activator of transcription 3/reactive oxygen species signaling pathway and inhibiting its downstream Na+/K+-ATPase activity.
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Apoptose , Leptina , Miócitos Cardíacos , Transdução de Sinais , Tecido Adiposo , Animais , Dieta Hiperlipídica , Janus Quinase 2 , Miócitos Cardíacos/citologia , Obesidade , Fosfatidilinositol 3-Quinases , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio , Fator de Transcrição STAT3 , ATPase Trocadora de Sódio-PotássioRESUMO
Background and Aim: Coronary artery disease (CAD) poses a worldwide health threat. Compelling evidence shows that pericardial adipose tissue (PAT), a brown-like adipose adjacent to the external surface of the pericardium, is associated with CAD. However, the specific molecular mechanisms of PAT in CAD are elusive. This study aims to characterize human PAT and explore its association with CAD. Methods: We acquired samples of PAT from 31 elective cardiac surgery patients (17 CAD patients and 14 controls). The transcriptome characteristics were assessed in 5 CAD patients and 4 controls via RNA-sequencing. Cluster profile R package, String database, Cytoscape were applied to analyze the potential pathways and PPI-network key to DEGS, whereas the hubgenes were predicted via Metascape, Cytohubba, and MCODE. We use Cibersort, ENCORI, and DGIDB to predict immunoinfiltration, mRNA-miRNA target gene network, and search potential drugs targeting key DEGs. The predictable hubgenes and infiltrating inflammatory cells were validated in 22 patients (12 CAD samples and 10 control samples) through RT-qPCR and immunohistochemistry. Results: A total of 147 different genes (104 up-regulated genes and 43 down-regulated genes) were identified in CAD patients. These different genes were associated with immunity and inflammatory dysfunction. Cibersort analysis showed monocytes and macrophages were the most common subsets in immune cells, whereas immunohistochemical results revealed there were more macrophages and higher proportion of M1 subtype cells in PAT of CAD patients. The PPI network and module analysis uncovered several crucial genes, defined as candidate genes, including Jun, ATF3, CXCR4, FOSB, CCl4, which were validated through RT-qPCR. The miRNA-mRNA network implicated hsa-miR-185-5p as diagnostic targets and drug-gene network showed colchicine, fenofibrate as potential therapeutic drugs, respectively. Conclusion: This study demonstrates that PAT is mainly associated with the occurrence of CAD following the dysfunction of immune and inflammatory processes. The identified hubgenes, predicted drugs and miRNAs are promising biomarkers and therapeutic targets for CAD.
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Tecido Adiposo/metabolismo , Doença da Artéria Coronariana/etiologia , Pericárdio/metabolismo , Tecido Adiposo/patologia , Idoso , Estudos de Casos e Controles , Doença da Artéria Coronariana/genética , Doença da Artéria Coronariana/metabolismo , Doença da Artéria Coronariana/cirurgia , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , MicroRNAs/genética , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Pericárdio/patologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA-Seq , Fatores de Risco , TranscriptomaRESUMO
BACKGROUND: Pericardial adipose tissue (PAT), a visceral fat depot directly located to the heart, is associated with atherosclerotic and inflammatory processes. The extent of PAT is related to the prevalence of coronary heart disease and might be used for cardiovascular risk prediction. This study aimed to determine the effect of smoking on the extent of PAT. METHODS: We retrospectively examined 1217 asymptomatic patients (490 females, age 58.3 ± 8.3 years, smoker n = 573, non-smoker n = 644) with a multislice CT scanner and determined the PAT volume. Coronary risk factors were determined at inclusion, and a multivariate analysis was performed to evaluate the influence of smoking on PAT independent from accompanying risk factors. RESULTS: The mean PAT volume was 215 ± 107 mL in all patients. The PAT volume in smokers was significantly higher compared to PAT volume in non-smokers (231 ± 104 mL vs. 201 ± 99 mL, p = 0.03). Patients without cardiovascular risk factors showed a significantly lower PAT volume (153 ± 155 mL, p < 0.05) compared to patients with more than 1 risk factor. Odds ratio was 2.92 [2.31, 3.61; p < 0.001] for elevated PAT in smokers. CONCLUSION: PAT as an individual marker of atherosclerotic activity and inflammatory burden was elevated in smokers. The finding was independent from metabolic risk factors and might therefore illustrate the increased inflammatory activity in smokers in comparison to non-smokers.
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AIMS: We examined the associations of pericardial adipose tissue with cardiac structures and cardiovascular risk factors in children. METHODS AND RESULTS: We performed a cross-sectional analysis in a population-based cohort study among 2892 children aged 10 years (2404 normal weight and 488 overweight/obese). Pericardial adipose tissue mass was estimated by magnetic resonance imaging (MRI) and indexed on height3. Left ventricular mass (LVM) and left ventricular mass-to-volume ratio (LMVR) were estimated by cardiac MRI. Cardiovascular risk factors included android adipose tissue percentage obtained by Dual-energy X-ray absorptiometry, blood pressure and glucose, insulin, cholesterol, and triglycerides concentrations. Adverse outcomes were defined as values above the 75 percentile. Median pericardial adipose tissue index was 3.6 (95% range 1.6-7.1) among normal weight and 4.7 (95% range 2.0-8.9) among overweight children. A one standard deviation (1 SD) higher pericardial adipose tissue index was associated with higher LMVR [0.06 standard deviation scores, 95% confidence interval (CI) 0.02-0.09], increased odds of high android adipose tissue [odd ratio (OR) 2.08, 95% CI 1.89-2.29], high insulin concentrations (OR 1.17, 95% CI 1.06-1.30), an atherogenic lipid profile (OR 1.22, 95% CI 1.11-1.33), and clustering of cardiovascular risk factors (OR 1.56, 95% CI 1.36-1.79). Pericardial adipose tissue index was not associated with LVM, blood pressure, and glucose concentrations. The associations showed largely the same directions but tended to be weaker among normal weight than among overweight children. CONCLUSION: Pericardial adipose tissue is associated with cardiac adaptations and cardiovascular risk factors already in childhood in both normal weight and overweight children.
Assuntos
Doenças Cardiovasculares , Tecido Adiposo/diagnóstico por imagem , Índice de Massa Corporal , Doenças Cardiovasculares/diagnóstico por imagem , Doenças Cardiovasculares/epidemiologia , Criança , Estudos de Coortes , Estudos Transversais , Fatores de Risco de Doenças Cardíacas , Humanos , Pericárdio/diagnóstico por imagem , Estudos Prospectivos , Fatores de Risco , Instituições AcadêmicasRESUMO
Pericardial adipose tissue (PAT), a visceral fat depot enveloping the heart, is an active endocrine organ and a source of free fatty acids and inflammatory cytokines. As in other fat adult tissues, PAT contains a population of adipose stem cells; however, whether these cells and/or their environment play a role in physiopathology is unknown. We analyzed several stem cell-related properties of pericardial adipose stem cells (PSCs) isolated from obese and ex-obese mice. We also performed RNA-sequencing to profile the transcriptional landscape of PSCs isolated from the different diet regimens. Finally, we tested whether these alterations impacted on the properties of cardiac mesoangioblasts isolated from the same mice. We found functional differences between PSCs depending on their source: specifically, PSCs from obese PSC (oPSC) and ex-obese PSC (dPSC) mice showed alterations in apoptosis and migratory capacity when compared with lean, control PSCs, with increased apoptosis in oPSCs and blunted migratory capacity in oPSCs and dPSCs. This was accompanied by different gene expression profiles across the cell types, where we identified some genes altered in obese conditions, such as BMP endothelial cell precursor-derived regulator (BMPER), an important regulator of BMP-related signaling pathways for endothelial cell function. The importance of BMPER in PSCs was confirmed by loss- and gain-of-function studies. Finally, we found an altered production of BMPER and some important chemokines in cardiac mesoangioblasts in obese conditions. Our findings point to BMPER as a potential new regulator of PSC function and suggest that its dysregulation could be associated with obesity and may impact on cardiac cells.