Detecting human coronary inflammation by imaging perivascular fat.

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.

A prospective study of external stenting of saphenous vein grafts to the right coronary artery: the VEST II study.

OBJECTIVES: External stents significantly reduce intimal hyperplasia and improve lumen uniformity and flow pattern in saphenous vein grafts (SVG) 1 year after coronary artery bypass grafting. However, recent studies have shown that at 1 year there is a lower patency of externally stented SVG to the right coronary artery (RCA) (55-60%) when compared to the left sided coronary arteries (85-90%). In the current study, we investigated whether avoidance of both fixation of the external stent to the anastomoses and the use of metal clips to ligate SVG side branches would improve the early patency of externally stented SVG to the RCA. METHODS: Thirty patients received a SVG to the right territory supported with an external stent. Graft patency was confirmed at the end of surgery in all patients. The primary endpoint was SVG patency assessed by computed tomography angiography (CTA) at 3-6 months. Graft failure was defined as > 50% stenosis. RESULTS: Twenty-nine patients (96.6%) completed the follow up period and CT angiography data was available for a total of 43 SVGs, (29 supported and 14 unsupported SVGs) and 47 arterial grafts. Patency of stented SVGs was 86.2% (25/29 on CTA). All non-stented SVGs to the left territory were patent. Patency rates of the left internal mammary arteries and right internal mammary arteries grafts were 96.6% and 83.3%, respectively. CONCLUSIONS: Avoidance of both metallic clips to ligate side branches and of fixation of venous external support trial (VEST) stents to the anastomoses mark a significant improvement in patency of stented SVG to the right coronary territory.

Novel biomarkers assessing endothelial dysfunction: role of microRNAs.

Endothelial dysfunction reflected by reduced nitric oxide availability is nowadays considered as a causative factor of atherosclerosis. A variety of biomarkers has been used as indicators of endothelial dysfunction in cardiovascular disease. Discovered just over a decade ago, microRNAs have evoked a great deal of interest, due to their importance for many aspects of homeostasis and disease. miRNAs comprise a novel class of endogenous, single-stranded, short RNA sequences able to regulate gene expression by binding to complementary sequences on mRNAs According to a growing body of evidence, they have been implicated in the regulation of several human physiological processes. They have been shown to participate in cardiovascular disease pathogenesis including atherosclerosis and endothelial dysfunction and this may have important clinical implications.

Insight to the pathophysiology of stable angina pectoris.

Atherosclerosis is a chronic disease which mainly represents an inflammatory response in the vessels. Myocardial ischemia manifested by angina pectoris can be either acute or chronic and usually is a result of imbalance between myocardial oxygen supply and myocardial oxygen demand. Chronic stable angina is chest discomfort attributed to myocardial ischemia without the presence of necrosis and is the most common symptom encountered by emergency room physicians. A growing amount of data has shown that endothelial dysfunction, is now considered an important early event in the development of atherosclerosis, while in the absence of angiographically obstructive coronary artery disease, anginal chest pain is often attributed to microvascular coronary dysfunction. Moreover, atheroma formation and in turn, atherosclerotic plaques seem to affect coronary flow, given that multivessel flow-limiting obstructions are observed in patients with chronic coronary syndrome. Morphological changes of diseased arteries related to significant atherosclerosis, such as vascular remodeling may also result in stable angina or claudication. However, several issues with respect to the comprehension of the pathophysiology of the chronic coronary syndrome have not been fully elucidated.

Targeting myocardial metabolism for the treatment of stable angina.

The goals of pharmacological treatment of stable angina pectoris are to improve quality of life by reducing the severity and/or frequency of symptoms and also the long-term prognosis. Patients with coronary artery disease have viable but dysfunctional myocardium. The metabolism of the ischemic myocardium is characterized by a shift from fatty acid to glucose as a preferred substrate and a decline in the levels of ATP. Targeting myocardial metabolism as a pharmacologic approach for chronic angina is based on the concept that metabolic adaptive mechanisms during ischemia resemble fetal energy metabolism by shifting substrate use towards glucose metabolism. Potential pharmacologic approaches should target i) the suppression of lipolysis and the plasma fatty acid levels and subsequent uptake and oxidation by the heart, ii) direct inhibition of the enzymes of fatty acid beta-oxidation, iii) inhibition of carnitine palmitoyl transferase- I (CPT-1). Currently, there are no approved medications directly targeting myocardial metabolism. However, in the last two years a number of medications indirectly targeting cardiac metabolism have been tested in small clinical trials, and some of them appear to be promising potential therapies for stable angina. This review summarizes the main aspects of myocardial metabolism and focuses on the therapeutic approaches that could offer clinical benefit in patients with stable angina.

Novel risk factors related to stable angina.

Stable angina (SA) pectoris is a common and disabling disorder in patients with coronary artery disease (CAD), with increasing epidemiology and is associated with myocardial infarction and increased mortality. However, within the population of SA patients, an individual's prognosis can vary considerably. Except from conventional risk factors a variety of biomarkers have been evaluated for their prognostic significance in the settings of SA. Novel biomarkers associated with inflammatory status, such as C reactive protein and tumor necrosis factor alpha, with myocardial performance, such as B-type natriuretic peptide, with extracellular matrix remodeling, with vascular calcification such as osteoprotogerin and osteopontin, with myocardial ischemia, such as ischemia modified albumin have been associated with the progression of CAD and with the prognosis of SA patients. Despite the multiplicity of novel biomarkers there is lack of a clinical useful, highly specific for CAD biomarker with the ability to guide treatment decisions. In the context of this evidence in this review article we summarize the so far acquired knowledge of the most promising biomarkers and we discuss the major clinical correlations of novel risk factors with SA physical history, their predictive value for future cardiovascular events and their use in the treatment monitoring of this population.

Matrix metallopropteinases in heart failure.

Heart failure (HF) represents a complex multifactorial syndrome, characterized by crucial structural and functional abnormalities of the myocardium. Matrix metalloproteinases are associated with left ventricular dysfunction, adverse left ventricular remodelling and prognosis after acute myocardial infarction. There is a strong association between oxidative stress and MMPs in the pathophysiology of HF. As MMPs are strongly associated to the pathogenesis and pathophysiology of HF, several agents have been proposed as potential modulators of these molecules. Classical agents such as statins, angiotensin converting enzyme inhibitors (ACEIS) and beta-blockers and a variety of novel agents have been implicated in the pathogenesis and progression of heart failure via the matrix metalloproteinases pathway and consist of possible future therapeutic targets.

Matrix metalloproteinases in acute coronary syndromes: current perspectives.

Matrix metalloproteinases (MMPs) are a family of zinc metallo-endopeptidases secreted by cells and are responsible for much of the turnover of matrix components. Several studies have shown that MMPs are involved in all stages of the atherosclerotic process, from the initial lesion to plaque rupture. Recent evidence suggests that MMP activity may facilitate atherosclerosis, plaque destabilization, and platelet aggregation. In the heart, matrix metalloproteinases participate in vascular remodeling, plaque instability, and ventricular remodelling after cardiac injury. The aim of the present article is to review the structure, function, regulation of MMPs and to discuss their potential role in the pathogenesis of acute coronary syndromes, as well as their contribution and usefullness in the setting of the disease.

Novel therapeutic approaches targeting matrix metalloproteinases in cardiovascular disease.

Matrix metalloproteinases (MMPs), are proteinases that participate in extracellular matrix remodelling and degradation. Under normal physiological conditions, the activities of MMPs are regulated at the level of transcription, of activation of the pro-MMP precursor zymogens and of inhibition by endogenous inhibitors (tissue inhibitors of metalloproteinases; TIMPs). Alteration in the regulation of MMP activity is implicated in atherosclerotic plaque development, coronary artery disease and heart failure. The pathological effects of MMPs and TIMPs in cardiovascular diseases involve vascular remodelling, atherosclerotic plaque instability and left ventricular remodelling after myocardial infarction. Since excessive tissue remodelling and increased matrix metalloproteinase activity have been demonstrated during atherosclerotic lesion progression, MMPs represent a potential target for therapeutic intervention aimed at modification of vascular pathology by restoring the physiological balance between MMPs and TIMPs. This review discusses pharmacological approaches to MMP inhibition.

Novel agents targeting nitric oxide.

Nitric oxide (NO) is a soluble gas continuously synthesized from the amino acid L-arginine in endothelial cells by the constitutive calcium-calmodulin-dependent enzyme nitric oxide synthase (NOS). Endothelial dysfunction has been identified as a major mechanism involved in all the stages of atherogenesis. Evaluation of endothelial function seems to have a predictive role in humans, and therapeutic interventions improving nitric oxide bioavailability in the vasculature, may improve the long-term outcome in healthy individuals, high-risk subjects or patients with advanced atherosclerosis. Several therapeutic strategies (including statins, angiotensin converting enzyme inhibitors/angiotensin receptors blockers, insulin sensitizers, antioxidant compounds) are now available, targeting both the synthesis and oxidative inactivation of NO in human vasculature, reversing in that way endothelial dysfunction which is enhanced by the release of nitric oxide from the endothelium.

The role of nitric oxide on endothelial function.

The vascular endothelium is a monolayer of cells between the vessel lumen and the vascular smooth muscle cells. Nitric oxide (NO) is a soluble gas continuously synthesized from the amino acid L-arginine in endothelial cells by the constitutive calcium-calmodulin-dependent enzyme nitric oxide synthase (NOS). This substance has a wide range of biological properties that maintain vascular homeostasis, including modulation of vascular dilator tone, regulation of local cell growth, and protection of the vessel from injurious consequences of platelets and cells circulating in blood, playing in this way a crucial role in the normal endothelial function. A growing list of conditions, including those commonly associated as risk factors for atherosclerosis such as hypertension, hypercholesterolemia, smoking, diabetes mellitus and heart failure are associated with diminished release of nitric oxide into the arterial wall either because of impaired synthesis or excessive oxidative degradation. The decreased production of NO in these pathological states causes serious problems in endothelial equilibrium and that is the reason why numerous therapies have been investigated to assess the possibility of reversing endothelial dysfunction by enhancing the release of nitric oxide from the endothelium. In the present review we will discuss the important role of nitric oxide in physiological endothelium and we will pinpoint the significance of this molecule in pathological states altering the endothelial function.

Diabetes mellitus and vascular endothelial dysfunction: current perspectives.

Patients with diabetes mellitus (DM) have a high prevalence of coronary artery disease (CAD), as diabetes is implicated in the formation of atherosclerotic plaque. Endothelial dysfunction is one of the precursor key steps in the development of atherosclerosis in diabetic subjects. Decreased nitric oxide (NO) production, increased oxidative stress and impaired function of endothelial progenitor cells are the main mechanisms involved in the accelerated atherosclerotic process observed in type 2 DM patients. Therapeutic approaches including classic agents such as statins, angiotensinconverting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), antioxidants and novel agents such as tetrahydrobiopterin (BH4), asymmetric dimethylarginine (ADMA) and homocysteine (tHcy), have been implicated in order to ameliorate endothelial function of diabetic patients.

Pathophysiology of atherosclerosis: the role of inflammation.

Atherosclerosis is a disease of arteries and is characterized by endothelial dysfunction, vascular inflammation, and the build-up of lipids, cholesterol, calcium, and cellular debris within the intima of the vessel wall. A number of factors commonly characterized as "risk factors" for atherosclerosis have been identified to facilitate the development of atherosclerosis by decreasing NO bioavailability in the vascular endothelium. The serious clinical manifestations of atherosclerosis (including coronary heart disease, stroke, and peripheral vascular disease) augment the need of performing the appropriate diagnostic methods to the patients. The most important diagnostic methods include the usage of biochemical markers and the invasive and non-invasive imaging techniques assessing endothelial function. The main drug categories that have been proved to ameliorate the inflammatory state in atherosclerosis are angiotensin converting enzyme inhibitors/angiotensin receptors blockers, statins, and antioxidants.

Potential pathogenic inflammatory mechanisms of endothelial dysfunction induced by type 2 diabetes mellitus.

Insulin resistance and the vascular complications of diabetes include activation of the inflammation cascade, endothelial dysfunction, and oxidative stress. The comorbidities of diabetes, namely obesity, insulin resistance, hyperglycemia, hypertension and dyslipidemia collectively aggravate these processes while antihyperglycemic interventions tend to correct them. Increased C-reactive protein, interleukin 6, tumor necrosis factor alpha and especially interstitial cellular adhesion molecule-1, vascular cellular adhesion molecule-1, and E-selectin are associated with cardiovascular and non-cardiovascular complications of both type 1 and type 2 diabetes. We sought to review the clinical implications of the inflammation theory, including the relevance of inflammation markers as predictors of type 2 diabetes in clinical studies, and the potential treatments of diabetes, inferred from the pathophysiology.

Rosuvastatin but not ezetimibe improves endothelial function in patients with heart failure, by mechanisms independent of lipid lowering.

INTRODUCTION: Congestive heart failure (HF) is characterised by increased proinflammatory stimulation and impaired endothelial function. Statin treatment exerts a beneficial effect on endothelial function and inflammatory process in patients with atherosclerosis. However, its effect in patients with HF is not well studied. Therefore, in the present study we compared the effect of short-term treatment with rosuvastatin or ezetimibe on endothelial function in patients with HF. METHODS: In this double-blind, placebo controlled, cross-over trial, 22 patients with HF were randomised to receive ezetimibe 20 mg/d or rosuvastatin 10 mg/d for 4 weeks, with 4 weeks wash-out period between the two interventions. Endothelial function was evaluated by flow mediated dilation (FMD) in the brachial artery at the beginning and at the end of each treatment period. RESULTS: There was no change in the baseline brachial diameter after treatment with either ezetimibe (p=NS) or rosuvastatin (p=NS). However, there was a significant improvement of FMD in the rosuvastatin group (p<0.05) but not in the ezetimibe group (p=NS). The changes in lipid levels were similar between groups (p=NS). The change in FMD was not significantly correlated with the decrease of serum LDL in either the ezetimibe or rosuvastatin treated groups. CONCLUSIONS: Rosuvastatin improves endothelial function in patients with congestive heart failure, by mechanisms independent of lipid-lowering. On the contrary, lipid-lowering treatment achieved by ezetimibe is unable to affect endothelial function in these patients. These findings indicate a direct beneficial effect of statins in patients with congestive heart failure, further to lipid-lowering.