Adipokine Imbalance in the Pericardial Cavity of Cardiac and Vascular Disease Patients

Aim Obesity and especially hypertrophy of epicardial adipose tissue accelerate coronary atherogenesis. We aimed at comparing levels of inflammatory and atherogenic hormones from adipose tissue in the pericardial fluid and circulation of cardiovascular disease patients. Methods and Results Venous plasma (P) and pericardial fluid (PF) were obtained from elective cardiothoracic surgery patients (n = 37). Concentrations of leptin, adipocyte fatty acid-binding protein (AFABP) and adiponectin (APN) were determined by enzyme-linked immunosorbent assays (ELISA). The median concentration of leptin in PF (4.3 (interquartile range: 2.8-9.1) mu g/L) was comparable to that in P (5.9 (2.2-11) mu g/L) and these were significantly correlated to most of the same patient characteristics. The concentration of A-FABP was markedly higher (73 (28-124) versus 8.4 (5.2-14) mu g/L) and that of APN was markedly lower (2.8 (1.7-4.2) versus 13 (7.2-19) mg/L) in PF compared to P. APN in PF was unlike in P not significantly related to age, body mass index, plasma triglycerides or coronary artery disease. PF levels of APN, but not A-FABP, were related to the size of paracardial adipocytes. PF levels of APN and A-FABP were not related to the immunoreactivity of paracardial adipocytes for these proteins. Conclusion In cardiac and vascular disease patients, PF is enriched in A-FABP and poor in APN. This adipokine microenvironment is more likely determined by the heart than by the circulation or paracardial adipose tissue.published_or_final_versio

Measuring non-polyaminated lipocalin-2 for cardiometabolic risk assessment

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A new class of glycomimetic drugs to prevent free fatty acid-induced endothelial dysfunction

Background: Carbohydrates play a major role in cell signaling in many biological processes. We have developed a set of glycomimetic drugs that mimic the structure of carbohydrates and represent a novel source of therapeutics for endothelial dysfunction, a key initiating factor in cardiovascular complications. Purpose: Our objective was to determine the protective effects of small molecule glycomimetics against free fatty acid­induced endothelial dysfunction, focusing on nitric oxide (NO) and oxidative stress pathways. Methods: Four glycomimetics were synthesized by the stepwise transformation of 2,5­dihydroxybenzoic acid to a range of 2,5­substituted benzoic acid derivatives, incorporating the key sulfate groups to mimic the interactions of heparan sulfate. Endothelial function was assessed using acetylcholine­induced, endotheliumdependent relaxation in mouse thoracic aortic rings using wire myography. Human umbilical vein endothelial cell (HUVEC) behavior was evaluated in the presence or absence of the free fatty acid, palmitate, with or without glycomimetics (1µM). DAF­2 and H2DCF­DA assays were used to determine nitric oxide (NO) and reactive oxygen species (ROS) production, respectively. Lipid peroxidation colorimetric and antioxidant enzyme activity assays were also carried out. RT­PCR and western blotting were utilized to measure Akt, eNOS, Nrf­2, NQO­1 and HO­1 expression. Results: Ex vivo endothelium­dependent relaxation was significantly improved by the glycomimetics under palmitate­induced oxidative stress. In vitro studies showed that the glycomimetics protected HUVECs against the palmitate­induced oxidative stress and enhanced NO production. We demonstrate that the protective effects of pre­incubation with glycomimetics occurred via upregulation of Akt/eNOS signaling, activation of the Nrf2/ARE pathway, and suppression of ROS­induced lipid peroxidation. Conclusion: We have developed a novel set of small molecule glycomimetics that protect against free fatty acidinduced endothelial dysfunction and thus, represent a new category of therapeutic drugs to target endothelial damage, the first line of defense against cardiovascular disease

New-onset of postoperative atrial fibrillation is likely to recur in the absence of other triggers

Jesper Park-Hansen,1 Anders M Greve,2,3 Johan Clausen,1 Susanne J Holme,4 Christian L Carranza,4 Akhmadjon Irmukhamedov,5 Lubna Sabah,1 Qing Lin,1 Anne Sofie Madsen,1 Helena Domínguez1,2 1Department of Cardiology, Bispebjerg/Frederiksberg University Hospital, Copenhagen, Denmark; 2Department of Biomedicine, Faculty of Health and Medical Sciences, 3Department of Cardiology, Herlev/Gentofte University Hospital, Copenhagen, Denmark; 4Department of Thoracic Surgery, Rigshospitalet, Copenhagen, Denmark; 5Department of Thoracic Surgery, Odense University Hospital, Odense, Denmark Background: Incident atrial fibrillation (AF) is reported in 10%–65% of patients without previous AF diagnosis after open heart surgery. The risk of late AF recurrence after a postoperative AF onset is unclear, and it is controversial whether AF limited to the postoperative period should elicit oral anticoagulation (OAC) therapy. The primary objective of this study was to evaluate the long-term recurrence of AF in patients developing new-onset peri-procedural AF. Patients and methods: Patients (n=189) with available baseline and follow-up data included in Left Atrial Appendage Closure with Surgery trial were coded for known AF at baseline and for postoperative first-time AF diagnosis. AF occurrence was classified as follows: peri-procedural ≤7 days postoperatively, early >7 days but ≤3 months and late >3 months. Patients with no AF recurrence registered during follow-up were invited to undergo Holter monitoring. Results: A total of 163 (86.2%) patients had no history of AF. Among these, 80 (49.1%) developed new-onset peri-procedural AF. After a mean follow-up of 3.7±1.6 years, late AF occurred in 35 of the 80 (43.8%) patients who developed peri-procedural AF and in 6 additional patients (7.2%) who remained in sinus rhythm until discharge (hazard ratio [HR] 9.3, 95% CI 3.8–22.4, p<0.001). Patients with peri-procedural AF and early AF had 12.24 times higher risk of late AF (95% CI 4.76–31.45, p<0.001) as compared to the group with no postoperative AF. Conclusion: New-onset of AF after open heart surgery has a high rate of recurrence and should not be regarded as a self-limiting phenomenon secondary to surgery. Keywords: atrial fibrillation, postoperative atrial fibrillation, heart surger

Supplementary Material for: Elastin Organization in Pig and Cardiovascular Disease Patients' Pericardial Resistance Arteries

Peripheral vascular resistance is increased in essential hypertension. This involves structural changes of resistance arteries and stiffening of the arterial wall, including remodeling of the extracellular matrix. We hypothesized that biopsies of the human parietal pericardium, obtained during coronary artery bypass grafting or cardiac valve replacement surgeries, can serve as a source of resistance arteries for structural research in cardiovascular disease patients. We applied two-photon excitation fluorescence microscopy to study the parietal pericardium and isolated pericardial resistance arteries with a focus on the collagen and elastin components of the extracellular matrix. Initial findings in pig tissue were confirmed in patient biopsies. The microarchitecture of the internal elastic lamina in both the pig and patient pericardial resistance arteries (studied at a transmural pressure of 100 mm Hg) is fiber like, and no prominent external elastic lamina could be observed. This microarchitecture is very different from that in rat mesenteric arteries frequently used for resistance artery research. In conclusion, we add three-dimensional information on the structure of the extracellular matrix in resistance arteries from cardiovascular disease patients and propose further use of patient pericardial resistance arteries for studies of the human microvasculature

Imaging and modeling of acute pressure-induced changes of collagen and elastin microarchitectures in pig and human resistance arteries

The impact of disease-related changes in the extracellular matrix (ECM) on the mechanical properties of human resistance arteries largely remains to be established. Resistance arteries from both pig and human parietal pericardium (PRA) display a different ECM microarchitecture compared with frequently used rodent mesenteric arteries. We hypothesized that the biaxial mechanics of PRA mirror pressure-induced changes in the ECM microarchitecture. This was tested using isolated pig PRA as a model system, integrating vital imaging, pressure myography, and mathematical modeling. Collagenase and elastase digestions were applied to evaluate the load-bearing roles of collagen and elastin, respectively. The incremental elastic modulus linearly related to the straightness of adventitial collagen fibers circumferentially and longitudinally (both R-2 &gt;= 0.99), whereas there was a nonlinear relationship to the internal elastic lamina elastin fiber branching angles. Mathematical modeling suggested a collagen recruitment strain (means +/- SE) of 1.1 +/- 0.2 circumferentially and 0.20 +/- 0.01 longitudinally, corresponding to a pressure of similar to 40 mmHg, a finding supported by the vital imaging. The integrated method was tested on human PRA to confirm its validity. These showed limited circumferential distensibility and elongation and a collagen recruitment strain of 0.8 +/- 0.1 circumferentially and 0.06 +/- 0.02 longitudinally, reached at a distending pressure below 20 mmHg. This was confirmed by vital imaging showing negligible microarchitectural changes of elastin and collagen upon pressurization. In conclusion, we show here, for the first time in resistance arteries, a quantitative relationship between pressure-induced changes in the extracellular matrix and the arterial wall mechanics. The strength of the integrated methods invites for future detailed studies of microvascular pathologies.NEW &amp; NOTEWORTHY This is the first study to quantitatively relate pressure-induced microstructural changes in resistance arteries to the mechanics of their wall. Principal findings using a pig model system were confirmed in human arteries. The combined methods provide a strong tool for future hypothesis-driven studies of microvascular pathologies.</p