Mustafa Dinc

Endocan, a novel marker of endothelial dysfunction in patients with essential hypertension: comparative effects of amlodipine and valsartan

Abstract Vascular inflammation plays an important role in the pathophysiology of hypertension and high levels of endocan may reflect ongoing vascular inflammation in hypertensive patients. In the present hypothesis-generating study, we aimed at investigating the comparative effects of amlodipine and valsartan on endocan levels in newly diagnosed hypertensive patients. The study population consisted of 37 untreated hypertensive patients who were randomized to the two treatment arms. After baseline assessment, each patient was randomly allocated to either 10 mg daily of amlodipine (n = 18, 7 males) or 160 mg daily of valsartan (n = 19, 3 males) and treated for a 3-month period. Sphygmomanometric blood pressure (BP) and serum endocan were measured before and every 2 weeks during drug treatment. There was no statistically significant difference between the two treatment arms as far as baseline socio-demographic and clinical characteristics are concerned. After a 3-month treatment period, systolic and diastolic BP values significantly reduced by antihypertensive treatment (p < 0.001). Furthermore, endocan levels were significantly decreased in both treatment arms (p < 0.05). However, amlodipine caused a greater percent decrease in circulating endocan levels compared with valsartan at the end of the treatment period. Both drugs reduced high sensitivity C-reactive protein values. However, the statistical significant difference vs baseline was achieved only in the group treated with amlodipine. No correlation was found between endocan plasma levels and BP reduction. The results of this hypothesis-generating study suggest that amlodipine and valsartan decrease endocan levels in newly diagnosed hypertensive patients. The effects, which are more evident with amlodipine, may contribute to the anti-inflammatory effects exerted by the two drugs on the vascular target.

Endothelial dysfunction, insulin resistance and inflammation in congenital hypogonadism, and the effect of testosterone replacement

Patients with hypogonadism have poor cardiovascular and metabolic outcomes, and the effect of testosterone replacement therapy (TRT) is not clear. We investigated the presence of inflammation, insulin resistance and endothelial dysfunction in an unconfounded population of congenital hypogonadotrophic hypogonadism (CHH) and the effect of TRT on these subjects. A total of 60 patients with CHH (mean age 21.82±2.22 years) and 70 healthy control subjects (mean age 21.32±1.13 years) were enrolled. The demographic parameters, Asymmetric dimethylarginine (ADMA), TNF-like weak inducer of apoptosis (TWEAK), high sensitive C reactive protein (hs-CRP) and homeostatic model assessment of insulin resistance (HOMA-IR) levels were measured before and after TRT. The patients had higher Waist Circumferences (WC) (p=0.009), Diastolic Blood Pressures (p=0.02), Triglycerides (p=0.03), ADMA, insulin and HOMA-IR levels (p<0.001 for all) and lower TWEAK levels (p<0.001), compared to the healthy controls. After 5.56 ± 2.04 months of TRT, the patients had significantly elevated systolic blood pressures (p=0.01), body mass indexes and WC (p<0.001 and p=0.001 respectively) and decreased total and HDL cholesterol levels (p=0.032 and p<0.001 respectively). ADMA levels significantly increased (p=0.003), while the alterations in TWEAK, hsCRP and HOMA-IR were not significant. The results of the present study show that endothelial dysfunction, inflammation and insulin resistance are prevalent even in the very young subjects with CHH, who have no metabolic or cardiac problems at present. This increased cardiometabolic risk however, do not improve but even get worse after six months of TRT. Long term follow-up studies are warranted to investigate the unfavorable cardiometabolic effects of TRT.

Epicardial Fat Thickness and Cardio-Ankle Vascular Index without Other Inflammatory Markers May Not Provide Information to Clinicians about the Systemic Inflammation

ic syndrome. Although the relationship between regular fatty liver disease and EFT is known [3] , it was not mentioned by the authors. Furthermore, in kidney disease patients, EFT has been positively associated with atherosclerosis, arterial stiffness (AS) and the presence of coronary artery calcification [4] . We feel it would have been useful if the authors had mentioned these factors, including liver and kidney function tests. CAVI is a novel marker of AS, which indicates the viscoelastic properties of the vessel wall. AS represents vascular damage and is a measure of the degree of atherosclerosis [5] . AS has received increased attention due to its role as an independent prognostic factor for hypertension, diabetes and heart failure. Increased AS is a common indicator of atherosclerotic involvement of the vascular structure, indicating CAD, cerebrovascular disease and peripheral arterial disease [6] . EFT and AS can be affected by atherosclerotic risk factors such as alcohol consumption, hypothyroidism, impaired glucose tolerance and higher inflammatory status such as an inflammatory disease, cardiac syndrome X and infection [7] . Unfortunately, in the present study the authors did not mention some of these posDear Editor, We read the article ‘Relation of epicardial fat thickness and cardio-ankle vascular index to complexity of coronary artery disease in nondiabetic patients’ written by Gökdeniz et al. [1] with great interest. The authors aimed to evaluate the relation of epicardial fat thickness (EFT) and cardioankle vascular index (CAVI) with coronary artery disease (CAD) complexity, which was assessed by SYNTAX score (SS) in nondiabetic patients undergoing coronary angiography for suspected CAD. They concluded that EFT assessed by echocardiography and CAVI measurements were significantly correlated with CAD complexity evaluated by SS. EFT and CAVI were found to be independent predictors of high SS. However, diagnostic accuracy of EFT and CAVI measurements for the prediction of intermediate-high SS was found to be comparable in nondiabetic patients undergoing coronary angiography for suspected CAD. We express thanks to the authors for their contributions to the present study, which was successfully designed and documented. Cardiovascular diseases are the most important causes of mortality and morbidity in developed countries worldwide [2] . EFT measured by echocardiography has been shown to be associated with metabolReceived: January 18, 2013 Accepted: January 22, 2013 Published online: April 19, 2013

Arterial stiffness should be evaluated with other inflammatory markers in patients with subclinical hypothyroidism

W e read the article “Assessment of the elasticity properties of the ascending aorta in patients with subclinical hypothyroidism by tissue Doppler imaging” by Mustafa Yurtdas and cols. with great interest (1). The authors aimed to investigate whether aortic elastic properties were affected in subclinical hypothyroidism (SCH) using tissue Doppler imaging (TDI). They concluded that SCH is associated with impaired elasticity of the ascending aorta. Elastic properties of the ascending aorta can be directly evaluated by the reproducible measurement of the upper wall movements of the ascending aorta by TDI in SCH patients. We are grateful to the authors for their contribution in a successfully designed and documented study. Cardiovascular diseases are the most important causes of mortality and morbidity in developed countries worldwide. SCH is associated as independent of classical risk factors for atherosclerosis (2). SCH is also related to an increased risk of CAD events and CAD mortality in patients with high thyroid stimulating hormone levels (≥ 10 mIU/L) (3). Arterial stiffness represents the viscoelastic properties of the vessel wall, indicates vascular damage, and is a measure of the degree of atherosclerosis (4). It has received increased attention due to its role as an independent prognostic factor for hypertension, chronic kidney disease, diabetes, and heart failure. Increased arterial stiffness is a common indicator of atherosclerotic involvement of the vascular structure, indicating CAD, cerebrovascular disease, and peripheral arterial disease. It can also be affected by the atherosclerotic risk factors, such as smoking, alcohol consumption, hypercholesterolemia, older age and autoimmune disease (5). In addition, some inflammatory disease, including systemic lupus erythematosus, psoriasis vulgaris, and Behcet disease may be related to arterial stiffness parameters (6). As for this point of view, in the Yurtdas and cols. study, the authors did not mention some of the affecting factors. It would be better if they gave information about these factors. Furthermore, some medications, such as antihypertensive treatment, including angiotensin-converting enzyme inhibitors, angiotensin receptor blocker, statins, medications used for weight loss, and medical history of drug addiction may influence arterial stiffness parameters. It would be useful and results might be different, if the authors described these factors. Finally, arterial stiffness is a non-invasive method to assess endothelial dysfunction in clinical practice, and it can be affected by many factors (7). Arterial stiffness itself without other inflammatory markers may not provide information to clinicians about atherosclerosis of SCH patients (8). Thus, we think that it should 1 Department of Cardiology, Gulhane Medical Academy Ankara, Turkey 2 Department of Internal Medicine, Gulhane Medical Academy Ankara, Turkey

Is there any correlation between serum uric acid levels and right ventricular function parameters in patients with cardiovascular risk factors

Weread the article “Associations of serumuric acid levelswith arterial wave reflections and central systolic blood pressure” written by Hsu PF et al. with great interest [1]. The authors aimed to investigate the roles of fourmajor hemodynamic parameters of blood pressure, including arterial stiffness, wave reflections, cardiac output, and total peripheral resistance, in the association between uric acid and central systolic blood pressure (SBP-c). They showed that serum uric acid levels were significantly independently associated with wave reflections, which is the dominant determinant of SBP-c. I would like to appreciate the authors for this valuable study. Uric acid (UA) is the main end product of the metabolic breakdown of purine nucleotides. A large-scale epidemiologic study showed that hyperuricemia is associated with an increased coronary artery disease (CAD) and cardiovascular mortality in the general population [2]. Serum UA is an independent predictor for all major forms of death from cardiovascular disease including acute, subacute and chronic forms of CAD, heart failure and stroke in elderly, post-menopausalwomen [3]. Increasing levels of UA, even in subjects with normouricemia, were associated with increasing prevalence of cardiovascular risk factors [4]. It has been shown that UA inhibits nitric oxide production by vascular endothelial cells. Increased serum UA levels can lead to endothelial dysfunction and inflammation which may contribute to the echocardiographic abnormalities of left ventricle (LV). Krishnan E. analyzed the relationship between serumUA and subclinical markers of heart failure in participants in the Framingham Offspring Cohort and showed that hyperuricemia in young adults can be a marker for subsequent LVdysfunction [5]. A significant relationshipbetween serum UA and parameters of LV diastolic functionwas showed in patient with chronic heart failure [6]. Significant correlationswere observedbetween the serum UA levels and LV function parameters includingmitral inflow velocities and tissue Doppler-derived mitral annular diastolic velocities and tissue Doppler derived myocardial performance index in hypertensive patients [7]. Echocardiographic assessment of the right ventricle has been largely qualitative, because of the difficulty with estimating RV volume and function with two-dimensional echocardiography because of its unusual shape [8]. Although right ventricular function is an important role for better cardiac global function, there is no study about effects of UA on right ventricular quantitative functions. Right ventricular function can be assessed echocardiographically by using several parameters including right ventricular index of myocardial performance, tricuspid annular plane systolic excursion, myocardial acceleration during isovolumic contraction, right ventricular fractional area change, tissue Doppler-derived tricuspid lateral annular systolic velocity, and longitudinal strain and strain rate [9]. Future prospective trials are needed to show whether hyperuricemia in patients with cardiovascular risk factors is associated with right ventricular dysfunction.

Oxidative stress status in congenital hypogonadism: an appraisal

Abstract Patients with hypogonadism are at increased risk of cardiac and metabolic diseases. However, the pathogenesis of increased cardiometabolic risk in patients with hypogonadism is not clear. Oxidative stress plays an important role in the pathogenesis of cardiometabolic diseases. This study aimed to investigate possible differences in oxidative stress conditions between patients with hypogonadism and healthy controls. In this study, 38 male patients with congenital hypogonadotropic hypogonadism (CHH) (mean age: 21.7 ± 1.6 years) and 44 healthy male controls (mean age: 22.3 ± 1.4 years) with almost equal body mass index were enrolled. The demographic parameters, follicle-stimulating hormone (FSH), luteinizing hormone (LH), total and free testosterone, homeostatic model assessment of insulin resistance (HOMA-IR) and oxidative stress parameters, such as superoxide dismutase, catalase (CAT), glutathione peroxidase (GPx) and malondialdehyde (MDA), were compared between both groups. Compared to the healthy controls, triglycerides (p = .02), insulin levels, HOMA-IR values, CAT activities and MDA levels (p < .001 for all) were significantly higher and HDL cholesterol (p = .04), total and free testosterone, FSH, LH levels and GPx activity were significantly lower (p < .001 for all) in patients with CHH. There were significant correlations between total testosterone levels and CAT activity (r = −.33 p = .01), GPx activity (r = .36 p = .007) and MDA (r = −.47 p < .001) levels. The results of this study showed that young and treatment-naïve patients with congenital hypogonadism had an increased status of oxidative stress.

Add on Exenatide Treatment is Beneficial in Poorly Controlled Obese Type 2 Diabetics under Intensive Insulin Regimens.

Background: Intensive insulin treatment is bothersome in obese patients with type 2 diabetes mellitus. High insulin dosages further increase weight gain and the risk of hypoglycemia. Glucagon like peptide-1 receptor agonists decrease the insulin need, cause weight loss and reduce the risk of hypoglycemia. There is limited data about the effect of exenatide on obese diabetics under intensive insulin regimens. Methods: This retrospective case series report the clinical outcomes of 23 obese (13 morbidly obese) patients with uncontrolled type 2 diabetes mellitus (Age=59±10.44 years, body mass index 41.1±6.8 kg/m2, HbA1c 9.9±1.5%), under high dose (94.1±39.6 unit) intensive insulin. Exenatide twice daily was added for a mean follow-up period of 11.22±7.01 (3-30) months. Intensive insulin regimens were continued in 7 patients while the others were switched to basal insulin during the follow-up. Results: During the follow-up, mean HbA1c levels of the patients significantly improved (p=0.019), along with the significant decrease in body mass index and the total insulin need (p<0.001 for both). Baseline insulin dosages were significantly higher in the intensive regimen group (p=0.013) while other demographical and clinical characteristics were similar. No significant difference was present between the groups regarding the alterations of HbA1c, body mass index and the reduction in total insulin dosages. Conclusion: Add on exenatide appears to be a rational treatment modality in uncontrolled obese patients with type 2 diabetes mellitus despite intensive insulin regimens. Further prospective randomized studies with longer follow-up periods are recommended.

Visceral adiposity index and triglyceride/high-density lipoprotein cholesterol ratio in hypogonadism

Background Cardiometabolic risk is high in patients with hypogonadism. Visceral adiposity index (VAI) and triglyceride/high-density lipoprotein cholesterol (TG/HDL-C) ratio are the practical markers of atherosclerosis and insulin resistance and independent predictors of cardiaovascular risk. To date, no study has evaluated VAI levels and TG/HDL-C ratio in hypogonadism. Subjects and methods A total of 112 patients with congenital hypogonadotrophic hypogonadism (CHH) (mean age, 21.7 ± 2.06 years) and 124 healthy subjects (mean age, 21.5 ± 1.27 years) were enrolled. The demographic parameters, VAI, TG/HDL-C ratio, asymmetric dimethylarginine (ADMA), high-sensitivity C-reactive protein (hs-CRP), and homeostatic model assessment of insulin resistance (HOMA-IR) levels were measured for all participants. Results The patients had higher total cholesterol (p = 0.04), waist circumference, triglycerides, insulin, and HOMA-IR levels (p = 0.001 for all) than the healthy subjects. VAI and ADMA and TG/HDL-C levels were also higher in patients than in healthy subjects (p < 0.001 for all). VAI was weakly correlated with ADMA (r = 0.27, p = 0.015), HOMA-IR (r = 0.22, p = 0.006), hs-CRP (r = 0.19, p = 0.04), and total testosterone (r = -0.21, p = 0.009) levels, whereas TG/HDL-C ratio was weakly correlated weakly with ADMA (r = 0.30, p = 0.003), HOMA-IR (r = 0.22, p = 0.006), and total testosterone (r = -0.16, p = 0.03) levels. Neither VAI nor TG/HDL-C ratio determined ADMA, HOMA-IR, and hs-CRP levels. Conclusions The results of this study demonstrate that patients with hypogonadism have elevated VAI and TG/HDL-C ratio. These values are significantly correlated with the surrogate markers of endothelial dysfunction, inflammation, and insulin resistance. However, the predictive roles of VAI and TG/HDL-C ratio are not significant. Prospective follow-up studies are warranted to clarify the role of VAI and TG/HDL-C ratio in predicting cardiometabolic risk in patients with hypogonadism.

Lifestyle Change Important for Patients With Hypertension and Cardiovascular Diseases

As we know, hypertension is quite common and is a preventable public health problem, which is one of the major causes of death. It has been shown to be very important in the development of CVD-related deaths, especially in recent studies. 2 Increased endothelial dysfunction, vascular inflammation, and atherosclerosis have mainly been blamed for the development of CVD. Chronic renal failure is quite common and is recently frequently seen together with increased CVD risks. 3 In this study, a relationship between eGFR and the presence of CVD and all-cause mortality is discussed in male hypertensive patients. However, the demographic data of the patients in the study seems to be a bit superficial. As an example, because cigarette smoking has a very strong association with CVD, 4 it would be better if the pack per year was given instead of just classifying smoking rates as daily and occasional. Thus, those patients would be understood to be heavy smokers or light smokers. However, alcohol intake, holding an especially important place in the development of CVD, was not mentioned and it is not clear whether the group drank alcohol heavily or socially. In addition, a change in lifestyle was applied to a portion of patients; however, what level and how they were implemented; how much exercise they performed, ie, how many days a week; and whether there were any restrictions in salt intake was not mentioned. 5 Clearing the difference between these patients and patients who received lifestyle changes would add more to the study results.

Increased Endothelial Dysfunction and Insulin Resistance in Patients with Klinefelter Syndrome

BACKGROUND AND OBJECTIVE Patients with Klinefelter Syndrome (KS) have increased cardiometabolic risk however the pathogenesis is not clear. We investigated the presence of endothelial dysfunction, insulin resistance and inflammation in an unconfounded population of KS. METHODS A total of 32 patients with KS (mean age 21.59 ± 1.66 years) and 33 healthy control subjects (mean age: 22.15 ± 1.03 years) were enrolled. The demographic parameters, Asymmetric dimethylarginine (ADMA), homeostatic model assessment of insulin resistance (HOMA-IR) index and highsensitivity C-reactive protein (hs-CRP) levels were measured. RESULTS The patients had higher Follicle Stimulating Hormone (FSH), Luteinizing Hormone (LH), insulin, HOMA-IR and ADMA levels (p < 0.001 for all) and lower High Density Lipoprotein Cholesterol (HDL-C) and total testosterone levels (p=0.002 and p<0.001, respectively), compared to the healthy controls. Total testosterone levels were significantly negatively correlated to ADMA (r = - 0.479, p < 0,001), hs-CRP (r = -0.291, p = 0.034) and positively correlated to HDL-C (r = 0.429, p = 0.001) levels. The multivariate analysis has shown that total testosterone (β = -0.412, p = 0.001) and TG (β = 0.332, p = 0.009) levels were the significant independent determinants of the plasma ADMA levels. CONCLUSION The results of the present study show that endothelial dysfunction and insulin resistance are prevalent even in the very young subjects with KS, who have no metabolic or cardiac problems at present. Also, hypogonadism seems to play an important role for increased cardiometabolic risk in patients with KS.