Mounting evidence highlights the role of adipose tissue in the development of a systemic inflammatory state that contributes to obesity-associated vasculopathy and cardiovascular risk. Circulating mediators of inflammation participate in the mechanisms of vascular insult and atheromatous change, and many of these inflammatory proteins are secreted directly from adipocytes and adipose tissue-derived macrophages. Several factors linking obesity with an increased cardiovascular risk have been identified. The adipocyte-specific secretory protein adiponectin is a particularly promising candidate in this context. Its levels are decreased in obesity. Adiponectin may mediate some of its demonstrated cardioprotective effects through its anti-inflammatory properties. In addition to decreased expression of beneficial adipokines, secretion of a host of inflammatory factors from visceral adipose tissue may contribute to the increased cardiovascular risk associated with obesity. The cardioprotective effects of many of the most popular drug regimens corroborate these conclusions, demonstrating that along with improvements in other therapeutic end points, they mediate improvements in systemic inflammation. In some cases, these improvements are attributable to direct suppression of inflammatory signaling in adipocytes. The targeted suppression of various proinflammatory cascades in adipocytes specifically represents an exciting new therapeutic opportunity for the cardiovascular disease area.

Adipose Tissue, Inflammation, and Cardiovascular Disease

Background Endothelial function is impaired in coronary artery disease and may contribute to its clinical manifestations. Increased oxidative stress has been linked to impaired endothelial function in atherosclerosis and may play a role in the pathogenesis of cardiovascular events. This study was designed to determine whether endothelial dysfunction and vascular oxidative stress have prognostic impact on cardiovascular event rates in patients with coronary artery disease. Methods and Results Endothelium-dependent and -independent vasodilation was determined in 281 patients with documented coronary artery disease by measuring forearm blood flow responses to acetylcholine and sodium nitroprusside using venous occlusion plethysmography. The effect of the coadministration of vitamin C (24 mg/min) was assessed in a subgroup of 179 patients. Cardiovascular events, including death from cardiovascular causes, myocardial infarction, ischemic stroke, coronary angioplasty, and coronary or peripheral bypass operation...

Endothelial Dysfunction, Oxidative Stress, and Risk of Cardiovascular Events in Patients With Coronary Artery Disease

There are several well-documented functions of high-density lipoprotein (HDL) that may explain the ability of these lipoproteins to protect against atherosclerosis. The best recognized of these is the ability of HDL to promote the efflux of cholesterol from cells. This process may minimize the accumulation of foam cells in the artery wall. However, HDL has additional properties that may also be antiatherogenic. For example, HDL is an effective antioxidants. The major proteins of HDL, apoA-I and apoA-II, as well as other proteins such as paraoxonase that cotransport with HDL in plasma, are well-known to have antioxidant properties. As a consequence, HDL has the capacity to inhibit the oxidative modification of low-density lipoprotein (LDL) in a process that reduces the atherogenicity of these lipoproteins. HDL also possesses other antiinflammatory properties. By virtue of their ability to inhibit the expression of adhesion molecules in endothelial cells, they reduce the recruitment of blood monocytes into the artery wall. These antioxidant and antiinflammatory properties of HDL may be as important as its cholesterol efflux function in terms of protecting against the development of atherosclerosis.

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Antiinflammatory Properties of HDL

A key event in atherosclerosis is a maladaptive inflammatory response to subendothelial lipoproteins. A crucial aspect of this response is a failure to resolve inflammation, which normally involves the suppression of inflammatory cell influx, effective clearance of apoptotic cells and promotion of inflammatory cell egress. Defects in these processes promote the progression of atherosclerotic lesions into dangerous plaques, which can trigger atherothrombotic vascular disease, the leading cause of death in industrialized societies. In this Review I provide an overview of these concepts, with a focus on macrophage death and defective apoptotic cell clearance, and discuss new therapeutic strategies designed to boost inflammation resolution in atherosclerosis.

Macrophage death and defective inflammation resolution in atherosclerosis.

Vascular endothelial function is essential for maintenance of health of the vessel wall and for vasomotor control in both conduit and resistance vessels. These functions are due to the production of numerous autacoids, of which nitric oxide (NO) has been the most widely studied. Exercise training has been shown, in many animal and human studies, to augment endothelial, NO-dependent vasodilatation in both large and small vessels. The extent of the improvement in humans depends upon the muscle mass subjected to training; with forearm exercise, changes are restricted to the forearm vessels while lower body training can induce generalized benefit. Increased NO bioactivity with exercise training has been readily and consistently demonstrated in subjects with cardiovascular disease and risk factors, in whom antecedent endothelial dysfunction exists. These conditions may all be associated with increased oxygen free radicals which impact on NO synthase activity and with which NO reacts; repeated exercise and shear stress stimulation of NO bioactivity redresses this radical imbalance, hence leading to greater potential for autacoid bioavailability. Recent human studies also indicate that exercise training may improve endothelial function by up-regulating eNOS protein expression and phosphorylation. While improvement in NO vasodilator function has been less frequently found in healthy subjects, a higher level of training may lead to improvement. Regarding time course, studies indicate that short-term training increases NO bioactivity, which acts to homeostatically regulate the shear stress associated with exercise. Whilst the increase in NO bioactivity dissipates within weeks of training cessation, studies also indicate that if exercise is maintained, the short-term functional adaptation is succeeded by NO-dependent structural changes, leading to arterial remodelling and structural normalization of shear. Given the strong prognostic links between vascular structure, function and cardiovascular events, the implications of these findings are obvious, yet many unanswered questions remain, not only concerning the mechanisms responsible for NO bioactivity, the nature of the cellular effect and relevance of other autacoids, but also such practical questions as the optimal intensity, modality and volume of exercise training required in different populations.

https://physoc.onlinelibrary.wiley.com/doi/pdf/10.1113/jphysiol.2004.068197

Effect of exercise training on endothelium‐derived nitric oxide function in humans

Der Einsatz des intravaskulären Ultraschalls in der kardiologisch-interventionellen Praxis

Effect of Dexamethasone-Eluting Stents on Systemic Inflammatory Response in Patients With Unstable Angina Pectoris or Recent Myocardial Infarction Undergoing Percutaneous Coronary Intervention

A remodeling, or compensatory vessel enlargement, has been recognized to be an important mechanism in the development of atherosclerosis. The phenomenon, originally described by Glagov et al,1 resembles a potential response of the artery to plaque growth. To maintain the lumen, arteries enlarge and maintain an adequate lumen size until plaque area occupies approximately 30% to 40% of the lumen.1–4 With higher degrees of stenosis, the artery loses the ability to compensate for further plaque growth, allowing plaques to encroach the lumen and to diminish blood flow. Remodeling has also been described in transplant vasculopathy and seems to be of relevance for the development of transplant vasculopathy.5 Intravascular ultrasound (IVUS) and histologic studies have revealed higher degrees of stenoses at branch points and bifurcations, and it has been shown that these regions are prone to specific conditions, exposing the arterial wall to altered amounts of flowand pressure-induced forces.6,7 Although the mechanisms involved in remodeling are not clear, there is increasing evidence that flow, shear, and tensile stress play important roles in its development.6–11 The purpose of this study was to analyze the dimensions and the remodeling behavior of arterial branch points by comparing them with those of nonbranching segments. In this manner, we tried to characterize whether alterations in this area influence the remodeling of arteries at these specific sites. • • • The study group consisted of 23 cardiac transplant recipients (18 men and 5 women; mean donor age 26 6 7 years) who underwent routine angiographic and IVUS follow-up. The mean age was 49 6 13 years at the time of transplantation; the mean time period between transplantation and study was 2.4 6 1.7 years. Twenty-five arterial segments (23 left anterior descending and 2 circumflex arteries) from these patients were selected following 3 strict sonographic criteria: (1) a high-quality visualization of at least 300 degrees of the arterial lumen and of the distinct wall layers, (2) visualization of both a coronary branch point and proximal and distal reference segments without further branchings between branch point and reference segments, and (3) a central and coaxial position of the IVUS catheter. Two hundred micrograms of intracoronary nitroglycerin were administered before the procedure in all patients. The imaging catheter was then advanced to the distal portion of the artery under fluoroscopic guidance, and IVUS imaging was performed during continuous manual pullback of the imaging catheter. IVUS studies were performed using a commercially available system (30 MHz, 3.2Fr, BS/SCIMED, Maple Grove, Minnesota). The catheter was pulled back manually at a speed of '0.5 mm/s, and the images were stored on videotapes for subsequent review and quantitative analysis. Quantitative measurements were obtained using a commercially available system (Tape Measure, Cupertino, California). The recorded ultrasound images were analyzed off-line following an established method13 using computerized planimetry. During image acquisition, video signals from a VHS videotape were converted with a frame grabber to 512 3 512 3 8-bit digital data and stored on a personal computer (Apple Macintosh, Cupertino, California). Then, the lumen area and the vessel area were traced in the IVUS image. The vessel area is the area encompassed by the external elastic lamina, i.e., the interface between the echo-dense tunica adventitia and the echo-lucent media. The cross-sectional lumen area, vessel area, and plaque 1 media area were detected automatically after the 2 contours were traced, calculating plaque area by subtracting lumen area from vessel area (Figure 1). The image with the widest lumen during 1 cardiac cycle was chosen for these measurements. Then the degree of compensatory enlargement was determined as remodeling ratio 5 vessel area/plaque area.8 Three cross sections of each arterial segment were analyzed (Figure 2): (1) 1 cross section just distal to a branch point (branch), (2) 1 reference cross section located proximal to the branch point (proximal), and (3) 1 reference cross section located distal to the branch point (distal). All measured values are presented as mean 6 SD. The relation between the 3 distinct groups of cross sections were analyzed by analysis of variance; for comparisons among 2 variables, a paired Student’s t test was used with Bonferroni correction for multiple comparisons. A statistical significance was accepted at a p value of ,0.05. Seventy-five coronary segments (25 branch, 50 reference) were analyzed in 23 patients. Proximal segments showed a vessel area of 18.84 6 4.94 mm, distal segments 17.31 6 4.69 mm, and at the branch 12.83 6 3.44 mm2. Thus, the vessel area not only of From the Department of Internal Medicine, Division of Cardiology, University of Innsbruck School of Medicine, Innsbruck, Austria. Dr. Schwarzacher’s address is: Department of Internal Medicine, Division of Cardiology, University of Innsbruck School of Medicine, Anichstrase 35, A-6020 Innsbruck, Austria. E-mail: Severin.Schwarzacher @uklibk.ac.at. Manuscript received August 29, 2000; revised manuscript received and accepted October 30, 2000.

Severin P. Schwarzacher

Papers

Der Einsatz des intravaskulären Ultraschalls in der kardiologisch-interventionellen Praxis

Effect of Dexamethasone-Eluting Stents on Systemic Inflammatory Response in Patients With Unstable Angina Pectoris or Recent Myocardial Infarction Undergoing Percutaneous Coronary Intervention

Intravascular ultrasound study in heart transplant recipients at proximal and distal branch points