Ioannis Akoumianakis

Mutual Regulation of Epicardial Adipose Tissue and Myocardial Redox State by PPAR-γ/Adiponectin Signalling.

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Detecting human coronary inflammation by imaging perivascular fat

Adipocyte size and lipid content in perivascular adipose tissue are inversely associated with coronary inflammation and atherosclerotic plaque burden in human patients. Picturing plaques and imaging inflammation To determine risk of future coronary artery disease, calcium content in vascular plaques is typically evaluated by coronary calcium scoring, which uses computerized tomography (CT) imaging. To detect inflammation and subclinical coronary artery disease (soft, noncalcified plaques), Antonopoulos et al. developed an alternative metric called the perivascular CT fat attenuation index (FAI). The perivascular FAI uses CT imaging of adipose tissue surrounding the coronary arteries to assess adipocyte size and lipid content. Larger, more mature adipocytes exhibit greater lipid accumulation, which is inversely associated with the FAI. Inflammation reduces lipid accumulation and slows preadipocyte differentiation. Imaging pericoronary fat in human patients after myocardial infarction revealed that unstable plaques had larger perivascular FAIs than stable plaques and that the FAI was greatest directly adjacent to the inflamed coronary artery. The perivascular FAI may be a useful, noninvasive method for monitoring vascular inflammation and the development of coronary artery disease. Early detection of vascular inflammation would allow deployment of targeted strategies for the prevention or treatment of multiple disease states. Because vascular inflammation is not detectable with commonly used imaging modalities, we hypothesized that phenotypic changes in perivascular adipose tissue (PVAT) induced by vascular inflammation could be quantified using a new computerized tomography (CT) angiography methodology. We show that inflamed human vessels release cytokines that prevent lipid accumulation in PVAT-derived preadipocytes in vitro, ex vivo, and in vivo. We developed a three-dimensional PVAT analysis method and studied CT images of human adipose tissue explants from 453 patients undergoing cardiac surgery, relating the ex vivo images with in vivo CT scan information on the biology of the explants. We developed an imaging metric, the CT fat attenuation index (FAI), that describes adipocyte lipid content and size. The FAI has excellent sensitivity and specificity for detecting tissue inflammation as assessed by tissue uptake of 18F-fluorodeoxyglucose in positron emission tomography. In a validation cohort of 273 subjects, the FAI gradient around human coronary arteries identified early subclinical coronary artery disease in vivo, as well as detected dynamic changes of PVAT in response to variations of vascular inflammation, and inflamed, vulnerable atherosclerotic plaques during acute coronary syndromes. Our study revealed that human vessels exert paracrine effects on the surrounding PVAT, affecting local intracellular lipid accumulation in preadipocytes, which can be monitored using a CT imaging approach. This methodology can be implemented in clinical practice to noninvasively detect plaque instability in the human coronary vasculature.

Unravelling the adiponectin paradox: novel roles of adiponectin in the regulation of cardiovascular disease

Adipose tissue (AT) has recently been identified as a dynamic endocrine organ secreting a wide range of adipokines. Adiponectin is one such hormone, exerting endocrine and paracrine effects on the cardiovascular system. At a cellular and molecular level, adiponectin has anti‐inflammatory, antioxidant and anti‐apoptotic roles, thereby mitigating key mechanisms underlying cardiovascular disease (CVD) pathogenesis. However, adiponectin expression in human AT as well as its circulating levels are increased in advanced CVD states, and it is actually considered by many as a ‘rescue hormone’. Due to the complex mechanisms regulating adiponectins biosynthesis in the human AT, measurement of its levels as a biomarker in CVD is highly controversial, given that adiponectin exerts protective effects on the cardiovascular system but at the same time its increased levels flag advanced CVD. In this review article, we present the involvement of adiponectin in CVD pathogenesis and we discuss its role as a clinical biomarker.

Perivascular adipose tissue as a regulator of vascular disease pathogenesis: identifying novel therapeutic targets

Adipose tissue (AT) is an active endocrine organ with the ability to dynamically secrete a wide range of adipocytokines. Importantly, its secretory profile is altered in various cardiovascular disease states. AT surrounding vessels, or perivascular AT (PVAT), is recognized in particular as an important local regulator of vascular function and dysfunction. Specifically, PVAT has the ability to sense vascular paracrine signals and respond by secreting a variety of vasoactive adipocytokines. Due to the crucial role of PVAT in regulating many aspects of vascular biology, it may constitute a novel therapeutic target for the prevention and treatment of vascular disease pathogenesis. Signalling pathways in PVAT, such as those using adiponectin, H2S, glucagon‐like peptide 1 or pro‐inflammatory cytokines, are among the potential novel pharmacological therapeutic targets of PVAT.

Predictive value of telomere length on outcome following acute myocardial infarction: evidence for contrasting effects of vascular vs. blood oxidative stress

Abstract Aims Experimental evidence suggests that telomere length (TL) is shortened by oxidative DNA damage, reflecting biological aging. We explore the value of blood (BTL) and vascular TL (VTL) as biomarkers of systemic/vascular oxidative stress in humans and test the clinical predictive value of BTL in acute myocardial infarction (AMI). Methods and results In a prospective cohort of 290 patients surviving recent AMI, BTL measured on admission was a strong predictor of all-cause [hazard ratio (HR) [95% confidence interval (CI)]: 3.21 [1.46–7.06], P = 0.004] and cardiovascular mortality (HR [95% CI]: 3.96 [1.65–9.53], P = 0.002) 1 year after AMI (for comparisons of short vs. long BTL, as defined by a T/S ratio cut-off of 0.916, calculated using receiver operating characteristic analysis; P adjusted for age and other predictors). To explore the biological meaning of these findings, BTL was quantified in 727 consecutive patients undergoing coronary artery bypass grafting (CABG), and superoxide (O2.-) was measured in peripheral blood mononuclear cells (PBMNC). VTL/vascular O2.- were quantified in saphenous vein (SV) and mammary artery (IMA) segments. Patients were genotyped for functional genetic polymorphisms in P22ph°x (activating NADPH-oxidases) and vascular smooth muscle cells (VSMC) selected by genotype were cultured from vascular tissue. Short BTL was associated with high O2.- in PBMNC (P = 0.04) but not in vessels, whereas VTL was related to O2.- in IMA (ρ = −0.49, P = 0.004) and SV (ρ = −0.52, P = 0.01). Angiotensin II (AngII) incubation of VSMC (30 days), as a means of stimulating NADPH-oxidases, increased O2.- and reduced TL in carriers of the high-responsiveness P22ph°x alleles (P = 0.007). Conclusion BTL predicts cardiovascular outcomes post-AMI, independently of age, whereas VTL is a tissue-specific (rather than a global) biomarker of vascular oxidative stress. The lack of a strong association between BTL and VTL reveals the importance of systemic vs. vascular factors in determining clinical outcomes after AMI.

Exploring the Crosstalk between Adipose Tissue and the Cardiovascular System

Obesity is a clinical entity critically involved in the development and progression of cardiovascular disease (CVD), which is characterised by variable expansion of adipose tissue (AT) mass across the body as well as by phenotypic alterations in AT. AT is able to secrete a diverse spectrum of biologically active substances called adipocytokines, which reach the cardiovascular system via both endocrine and paracrine routes, potentially regulating a variety of physiological and pathophysiological responses in the vasculature and heart. Such responses include regulation of inflammation and oxidative stress as well as cell proliferation, migration and hypertrophy. Furthermore, clinical observations such as the “obesity paradox,” namely the fact that moderately obese patients with CVD have favourable clinical outcome, strongly indicate that the biological “quality” of AT may be far more crucial than its overall mass in the regulation of CVD pathogenesis. In this work, we describe the anatomical and biological diversity of AT in health and metabolic disease; we next explore its association with CVD and, importantly, novel evidence for its dynamic crosstalk with the cardiovascular system, which could regulate CVD pathogenesis.

Impaired Vascular Redox Signalling in the Vascular Complications of Obesity and Diabetes Mellitus

SIGNIFICANCE Oxidative stress, a crucial regulator of vascular disease pathogenesis, may be involved in the vascular complications of obesity, systemic insulin resistance (IR), and diabetes mellitus (DM). Recent Advances: Excessive production of reactive oxygen species in the vascular wall has been linked with vascular disease pathogenesis. Recent evidence has revealed that vascular redox state is dysregulated in cases of obesity, systemic IR, and DM, potentially participating in the well-known vascular complications of these disease entities. CRITICAL ISSUES The detrimental effects of obesity and the metabolic syndrome on vascular biology have been extensively described at a clinical level. Further, vascular oxidative stress has often been associated with the presence of obesity and IR as well as with a variety of detrimental vascular phenotypes. However, the mechanisms of vascular redox state regulation under conditions of obesity and systemic IR, as well as their clinical relevance, are not adequately explored. In addition, the notion of vascular IR, and its relationship with systemic parameters of obesity and systemic IR, is not fully understood. In this review, we present all the important components of vascular redox state and the evidence linking oxidative stress with obesity and IR. FUTURE DIRECTIONS Future studies are required to describe the cellular effects and the translational potential of vascular redox state in the context of vascular disease. In addition, further elucidation of the direct vascular effects of obesity and IR is required for better management of the vascular complications of DM. Antioxid. Redox Signal. 00, 000-000.

Dipeptidyl peptidase IV inhibitors as novel regulators of vascular disease

Dipeptidyl peptidase IV (DPP-IV) has been revealed as an adipokine with potential relevance in cardiovascular disease (CVD), while clinically used DPP-IV inhibitors have demonstrated beneficial cardiovascular effects in several experimental studies. Perivascular adipose tissue (PVAT) is a unique adipose tissue depot in close anatomical proximity and bidirectional functional interaction with the vascular wall, which is a source of DPP-IV and its biology may be influenced by DPP-IV inhibition. Recently, DPP-IV inhibition has been associated with decreased local inflammation and oxidative stress both in the vascular wall and the PVAT, potentially regulating atherogenesis progression in vivo. DPP-IV inhibition may thus be a promising target in cardiovascular disease. However, the exact pleiotropic mechanisms that underlie the cardiovascular effects of DPP-IV inhibition need to be clarified, while the in vivo benefit of DPP-IV inhibition in humans remains unclear.

Overnight urinary isoprostanes as a marker of oxidative stress in obstructive sleep apnoea

Oxidative stress is thought to be of importance in the development of cardiovascular disease in obstructive sleep apnoea (OSA). However, our recent study [1] using data from two centres showed that markers of oxidative stress were not increased by the return of OSA caused by continuous positive airways pressure (CPAP) withdrawal for 2 weeks. Unexpectedly, we found decreased levels of urinary isoprostanes in early morning urine specimens and this, combined with increased levels of blood superoxide dismutase, raised the possibility that oxidative stress might be decreased by OSA. Urinary isoprostanes, a key biomarker of oxidative stress, are not increased by OSA during CPAP withdrawal http://ow.ly/grU8305ZX1s

Is stress response a new link between adipose tissue and atherogenesis? The role of HSPs/HSF1

This editorial refers to ‘Heat shock factor-1 knockout enhances cholesterol 7α-hydroxylase (CYP7A1) and multidrug transporter (MDR1) gene expressions to attenuate atherosclerosis’, by K. Krishnamurthy et al. , pp. 74–83. The role of lipids in atherogenesis is well established; subendothelial deposition of oxidized low-density lipoprotein (ox-LDL) initiates atherosclerotic plaque formation.1 Circulating cholesterol is regulated by its dietary intake and endogenous synthesis on one hand, and its elimination from the circulation via LDL-receptors/excretion in the bile on the other hand.2 Various lipid-lowering therapies targeting these regulatory mechanisms are used in patients with dyslipidaemias, significantly impacting cardiovascular risk. However, the residual risk after applying existing lipid-lowering strategies highlights the complexity of lipid metabolism and the necessity for broader understanding of the links between lipids and the cardiovascular system. Over the last decade, it became clear that adipose tissue is an active endocrine organ producing various adipocytokines, the secretory profile of which is dysregulated in cardiovascular and metabolic disease. Adipocyte differentiation, a process whereby small pre-adipocytes with little lipid content transform into large, differentiated lipid-rich adipocytes, is altered in cardiometabolic disease.3 Obesity-related diseases are characterized by adipose inflammatory infiltration, which prevents pre-adipocyte differentiation, affecting lipid and energy consumption/expenditure and modifying the secretory profile of the tissue.3 The literature on the roles …