Emmanuel Androulakis

Diabetes Mellitus-Associated Vascular Impairment: Novel Circulating Biomarkers and Therapeutic Approaches

It is widely accepted that diabetes mellitus (DM) impairs endothelial nitric oxide synthase activity as well as enhances the production of reactive oxygen species, thus resulting in diminished nitric oxide bioavailability and the consequent pro-atherogenetic alterations. Important biomarkers of the vasculature are related to endothelial dysfunction, to inflammatory and coagulation processes, and to oxidative stress in DM. Several therapeutic strategies might exert favorable effects on the vasculature of diabetic patients, such as insulin analogues, antihypertensive agents, statins, and hypoglycemic agents, whereas in spite of the prominent role of oxidative stress in diabetes, antioxidant therapy remains controversial. The use of specific biomarkers related to vascular function could be a useful therapeutic approach in such patients.

Fibrinogen and cardiovascular disease: genetics and biomarkers.

Several prospective epidemiological studies and clinical observations provided evidence regarding fibrinogen and coronary artery disease (CAD). Many of these studies firmly correlate fibrinogen with CAD. However, it is uncertain whether this relation is causal or reflects genetic variability and residual confounding by other risk factors. Several polymorphisms on fibrinogen chain genes affect its levels, however only few of the genetic variants are associated with increased cardiovascular risk. As regards the role of fibrinogen in myocardial infarction (MI) studies indicate that genetic variations have at best a modest impact on the process resulting in MI. Therefore, the screening of fibrinogen genes might not be useful for the assessment of the risk of MI. However, the findings that specific genotypes lead to specific differences in fibrinogen levels, but may not be linked to cardiovascular risk, complicates the hypothesis of causality of fibrinogen in the pathogenesis of cardiovascular disease.

Homoarginine in the shadow of asymmetric dimethylarginine: from nitric oxide to cardiovascular disease

It is well known that the endothelium maintains the vascular homeostasis. Importantly, endothelial dysfunction is regarded as a key early step in the development of atherosclerosis. Back in the early 1990s, it was found that asymmetric dimethylarginine (ADMA), an arginine metabolite derived from l-arginine (Arg) residues in proteins by asymmetric dimethylation on its guanidine group, is an endogenous inhibitor of nitric oxide (NO) synthase (NOS) isoforms. Inhibition of NO synthesis from Arg by the endothelial NOS isoform (eNOS) leads to endothelial dysfunction. Due to this action, ADMA participates in the pathophysiology of atherosclerosis and potentially contributes to cardiovascular events. Nowadays, homoarginine (hArg) is considered as a new key player in atherogenesis. hArg is a non-essential, non-proteinogenic amino acid which is synthesized from Arg by arginine:glycine amidinotransferase (AGAT). hArg is structurally related to Arg; formally, hArg is by one methylene (CH2) group longer than Arg, and may serve as a substrate for NOS, thus contributing to NO synthesis. For several decades, the pathophysiological role of hArg has been entirely unknown. hArg has been in the shadow of ADMA. Clinical studies have sought to investigate the relationship between circulating hArg levels and human disease states as well as cardiovascular prognosis. Recent studies indicate that hArg is actively involved in the vascular homeostasis, yet the underlying mechanisms are incompletely understood. In this article, we review the available literature regarding the role of ADMA and hArg in endothelial dysfunction and in cardiovascular disease as well as the possible associations between these endogenous Arg derivatives.

Novel therapeutic strategies in the management of arterial hypertension.

Essential hypertension is a disease with a major impact on health worldwide, thus control of blood pressure seems to be a key component of cardiovascular disease prevention. Despite considerable advances in the treatment of hypertension, effective management remains poor and new strategies to control high blood pressure and cardiovascular risk reduction are required. These seem to be divided into two major categories: those seeking to advance blood pressure-lowering efficacy of already existing agents, and others related to novel approaches, both pharmacological and non-pharmacological. Moreover, numerous clinical trials have evaluated the use of nutritional supplements in the prevention of cardiovascular diseases and in achievement of optimal blood pressure control. Additionally, the advent of interventional techniques, such as carotid baroreceptor stimulation and renal ablation of sympathetic nerve activity, seems to be proved effective in cases where medical management and lifestyle modifications are insufficient. Genetic technology, which has advanced tremendously over the past few years, could assist novel treatment options in hypertensive patients, such as RNA interference targeting hypertension-related genes. However, continued efforts must progress in these areas and the effects of therapeutic strategies in hypertensive patients need to be further explored in larger trials over a longer period of time.

Socioeconomic status and risk factors for cardiovascular disease: Impact of dietary mediators

It is well known that cardiovascular disease is the leading cause of mortality in the western societies. A number of risk factors such as family history, diabetes, hypertension, obesity, diabetes, smoking and physical inactivity are responsible for a significant proportion of the overall cardiovascular risk. Interestingly, recent data suggest there is a gradient in the incidence, morbidity and mortality of cardiovascular disease across the spectrum of socioeconomic status, as this is defined by educational level, occupation or income. Additionally, dietary mediators seem to play significant role in the pathogenesis of cardiovascular disease, mediating some of the discrepancies in atherosclerosis among different socioeconomic layers. Therefore, in the present article, we aim to review the association between socioeconomic status and cardiovascular disease risk factors and the role of different dietary mediators.

Combined effects of fibrinogen genetic variability on atherosclerosis in patients with or without stable angina pectoris: focus on the coagulation cascade and endothelial function.

BACKGROUNDnFibrinogen is a coagulation/inflammatory biomarker strongly associated with atherogenesis. Data have reported that the genetic variability on fibrinogen chains may affect the atherosclerotic process and the risk of coronary artery disease (CAD). We examined the combined effects of the G455A and the G58A fibrinogen genetic polymorphisms on prothrombotic profile, endothelial function and the risk of CAD in a Caucasian population.nnnMETHODSnWe recruited 422 patients with angiographically documented CAD and 277 controls matched for age and gender. The two polymorphisms were genotyped by polymerase chain reaction and restriction endonuclease digestion. Fibrinogen and D-Dimers levels, as well as factors (f) V, X activity were measured by standard coagulometry techniques. Endothelial function was assessed by the flow mediated dilatation (FMD) of the brachial artery.nnnRESULTSnThe two polymorphisms had no significant effect on the risk for CAD. Although the 58AA subjects had not significantly different levels of fibrinogen compared with the 58GG+GA in both groups (p=NS), we importantly found that the 455AA homozygosity was associated with increased fibrinogen levels not only in the control group (p=0.035), but also in the CAD group (p<0.001) compared to the G allele carriers. Moreover, both the 58AA (p=0.016) and 455AA homozygotes (p=0.022) presented with higher levels of D-Dimers in the CAD group. Interestingly, the 455AA homozygotes had increased fV activity in the CAD group (p=0.048). However, no significant effects were observed on fX activity and FMD.nnnCONCLUSIONSnBoth fibrinogen polymorphisms are capable to modify the atherosclerotic process via their effects on the coagulation cascade.

Genetic Predisposition to Left Ventricular Hypertrophy and the Potential Involvement of Cystatin-C in Untreated Hypertension

BACKGROUNDnThe angiotensinogen M235T and aldosterone synthase C-344T gene polymorphisms have been associated with cardiac and structure function. However, these associations in untreated hypertension remain unknown. We examined whether these variants determined both echocardiography indices and the potential associated underlying mechanisms, including cystatin-C and vascular inflammation.nnnMETHODSnThe study population consisted of 319 untreated patients and 191 healthy individuals. Polymorphisms were determined by polymerase chain reaction technique. Left cardiac indices of geometry and function were assessed by echocardiography. Cystatin-C, intracellular cell adhesion molecule 1, and vascular cell adhesion molecule 1 levels were measured by enzyme-linked immunosorbent assay, whereas high sensitivity C-reactive protein levels were measured by immunonephelometry.nnnRESULTSnThere was no significant interaction between the angiotensinogen genotypes on left ventricular mass index (LVMI) and diastolic function indices in all study groups. Regarding C-344T polymorphism, TT homozygous hypertensive subjects exhibited higher values of LVMI compared with C allele carriers (P = 0.02) and higher prevalence of concentric hypertrophy (P < 0.001). However, this polymorphism was not associated with variations in left atrial volume and diastolic dysfunction. Cystatin-C levels were correlated with LVMI values (r = 0.22; P = 0.002) and mean E/A ratio (r = -0.24; P < 0.001). Interestingly, a linear increase of LVMI with cyctatin-C quartiles has been revealed (F = 5.01; P < 0.001). Moreover, post hoc tests showed that increased levels of cystatin-C (above 75th percentile) were significantly different between both the first (P = 0.009) and the second quartile (P = 0.02).nnnCONCLUSIONSnWe have shown that C-344T potentially predicts higher values of LVMI and concentric hypertrophy in untreated hypertension, independently of renal function and subclinical inflammation. Increased levels of cystatin-C were correlated with higher LVMI values.

Lp-PLA2—A novel marker of atherosclerosis: To treat or not to treat?

Inflammatory process contributes significantly to the initiation, progression and rupture of atherosclerotic plaques [1]. A number of classic alongwith novel, which are still under investigation, inflammatory biomarkers, have been proposed during the last years, evaluating the contribution of inflammation in atherogenesis [2]. Data have demonstrated also that inflammatory biomarkersmay be able to predict cardiovascular disease (CVD) events [2]. Thus, apart from the widely studied C-reactive protein (CRP) and among several novel biomarkers examined for their role in CVD, lipoprotein-associated phospholipase A2 (Lp-PLA2) is an emerging inflammatory marker playing a key role in vascular inflammation and importantly in atherosclerosis evolution (Fig. 1). More specifically, Lp-PLA2 is an enzyme that hydrolyzes phospholipids to generate lysophospholipids as well as oxidized free fatty acids, while having a predictive role for future CVD events. Although there is an encouraging amount of Lp-PLA2-associated data, little is known about the involvement of Lp-PLA2 in the pathophysiology of atherosclerosis, CVD risk prediction, its association with cardiovascular indices and its potential as a therapeutic target for future medical treatments. In this issue of the Journal Charniot et al. [3] aimed to assess relationships between Lp-PLA2 levels, cardiac disease and treatments and to evaluate the association of Lp-PLA2 levels with the severity of angiographic coronary artery disease (CAD) and the extracoronary atherosclerosis. They reported that interpretation of Lp-PLA2 levels needs a good assessment of cardiac parameters and treatments, especially statins and ACEi/ARA2. In addition, Lp-PLA2 levels are significantly associated with coronary heart disease and with the extension

Genetic polymorphism M235T of angiotensinogen: Effects on endothelial function and arterial stiffness in hypertensives

[1] Gibson CM, Cannon CP, DaleyWL, et al. TIMI frame count: a quantitative method of assessing coronary artery flow. Circulation 1996;93:879–88. [2] Kunadian V, Harrigan C, Zorkun C, et al. Use of the TIMI frame count in the assessment of coronary artery blood flow andmicrovascular function over the past 15 years. J Thromb Thrombolysis 2009;27:316–28. [3] Porto I, Hamilton-Craig C, Brancati M, Burzotta F, Galiuto L, Crea F. Angiographic assessment of microvascular perfusion–myocardial blush in clinical practice. Am Heart J 2010;160:1015–22. [4] Korosoglou G, Haars A, Michael G, et al. Quantitative evaluation of myocardial blush to assess tissue level reperfusion in patients with acute ST-elevation myocardial infarction: incremental prognostic value compared with visual assessment. Am Heart J 2007;153:612–20. [5] Haeck JD, Gu YL, Vogelzang M, et al. Feasibility and applicability of computerassisted myocardial blush quantification after primary percutaneous coronary intervention for ST-segment elevation myocardial infarction. Catheter Cardiovasc Interv 2010;75:701–6. [6] Ungi T, Ungi I, Jonas Z, et al. Myocardium selective densitometric perfusion assessment after acute myocardial infarction. Cardiovasc Revasc Med 2009;10:49–54. [7] Ungi T, Zimmermann Z, Balazs E, et al. Vessel masking improves densitometric myocardial perfusion assessment. Int J Cardiovasc Imaging 2009;25:229–36. [8] Vijayalakshmi K, Ashton VJ, Wright RA, et al. Corrected TIMI frame count: applicability in modern digital catheter laboratories when different frame acquisition rates are used. Catheter Cardiovasc Interv 2004;63:426–32. [9] Gibson CM, Cannon CP,Murphy SA, et al. Relationship of TIMImyocardial perfusion grade to mortality after administration of thrombolytic drugs. Circulation 2000;101:125–30. [10] Spaan J, Kolyva C, van den Wijngaard J, et al. Coronary structure and perfusion in health and disease. Philos Transact A Math Phys Eng Sci 2008;366:3137–53. [11] Cannon III RO. Microvascular angina and the continuing dilemma of chest pain with normal coronary angiograms. J Am Coll Cardiol 2009;54:877–85. [12] Miller JM, Rochitte CE, Dewey M, et al. Diagnostic performance of coronary angiography by 64-row CT. N Engl J Med 2008;359:2324–36. [13] Wijns W, De Bruyne B, Vanhoenacker PK. What does the clinical cardiologist need from noninvasive cardiac imaging: is it time to adjust practices to meet evolving demands? J Nucl Cardiol 2007;14:366–70.

Effects of the C-344T aldosterone synthase gene variant on preclinical vascular alterations in essential hypertension

regulated kinase and angiotensin-converting enzyme in human atria during atrial fibrillation. J Am Coll Cardiol 2000;35:1669–77. [43] Kumagai K, Nakashima H, Urata H, et al. Effects of angiotensin II type 1 receptor antagonist on electrical and structural remodeling in atrial fibrillation. J Am Coll Cardiol 2003;41:2197–204. [44] Shimano M, Tsuji Y, Inden Y, et al. Pioglitazone, a peroxisome proliferators-activated receptor-gamma activator, attenuates atrial fibrosis and atrial fibrillation promotion in rabbits with congestive heart failure. Heart Rhythm 2008;5:451–9.