Atila Iyisoy

The Relation Between Atherosclerosis and the Neutrophil–Lymphocyte Ratio

Inflammation plays an important role in the pathophysiology of vascular disease. In this review, we consider the associations between the neutrophil–lymphocyte ratio (NLR; an indicator of inflammation) and vascular disease and its associated risk factors. The NLR has received attention due to its role as an independent prognostic factor for coronary artery disease. The NLR can also be affected by atherosclerotic risk factors, such as hypercholesterolemia, metabolic syndrome, diabetes, and hypertension. Importantly, it can predict mortality in cardiovascular diseases. There are also reports of a positive correlation between the NLR and commonly used inflammatory markers. Inflammation is important not only in pathophysiology but also clinical outcomes of many diseases. The NLR is a widely available, easily derived, and reproducible marker of inflammation. Unlike many other inflammatory markers, the NLR is inexpensive and readily available and it provides additional risk stratification beyond conventional risk scores.

Endocan--a novel inflammatory indicator in newly diagnosed patients with hypertension: a pilot study.

Endothelial dysfunction is regarded as the initial lesion in the development of atherosclerosis. Endocan, previously called endothelial cell–specific molecule 1 (ESM-1), is a new candidate immunoinflammatory marker that may be associated with cardiometabolic risk factors. Therefore, we assessed serum levels of endocan in newly diagnosed patients with untreated essential hypertension (HT). A total of 18 patients with HT and 23 normotensive control participants were included in the study. Serum endocan levels, carotid intima–media thickness (cIMT), and high-sensitivity C-reactive protein (hsCRP) were measured. Serum endocan levels were significantly higher in the HT group (P < .001). In patients with HT, serum endocan levels correlated positively with cIMT and hsCRP (r = .551, P < .001 and r = .644, P < .001, respectively). Our findings suggest that circulating endocan levels represent a new marker in patients with essential HT. Endocan may be a surrogate endothelial dysfunction marker and may have a functional role in endothelium-dependent pathological disorders.

Aortic Arterial Stiffness is a Moderate Predictor of Cardiovascular Disease in Patients With Psoriasis Vulgaris

Psoriasis is associated with an increased risk of atherosclerosis. Endothelial dysfunction is the critical early step in the process of atherogenesis, and it is commonly investigated by measuring arterial stiffness. We aimed to investigate the relationship between arterial stiffness and high-sensitivity C-reactive protein (hsCRP) in patients with psoriasis. A total of 32 patients with psoriasis and 35 patients with other skin diseases were included in the study. The hsCRP levels and arterial stiffness measurements were compared. Arterial stiffness was significantly different between the 2 groups (P = .01). Arterial stiffness was not associated with the duration of the disease or the disease activity (P = .34 and .64, respectively). In patients with psoriasis, arterial stiffness correlated positively with age, sex, body mass index, diastolic blood pressure, and hsCRP level (P < .05). These findings provide further evidence of a link between inflammation, premature atherosclerosis, and psoriasis.

Endocan: A novel inflammatory indicator in cardiovascular disease?

Endothelial dysfunction is considered as an early change in atherogenesis. Raised levels of systemic inflammatory markers are associated with cardiovascular disease (CVD). Endocan (previously known as endothelial cell specific molecule-1, ESM-1), is a potential immunoinflammatory marker that may be linked to CVD. Endocan is released by vascular endothelial cells in several organs. Endocan may play an important role in regulating cell adhesion and raised plasma levels may reflect endothelial dysfunction. Endocan levels are elevated in conditions such as chronic kidney disease, renal transplant rejection, tumor progression and hypertension. Endocan is a potential inflammatory and CVD marker. Further studies are needed to assess the relevance of endocan in clinical practice.

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.

Endocan and Atherosclerosis

We read with interest the letter by Aparci et al regarding our article entitled ‘‘Endocan—A Novel Inflammatory Indicator in Newly Diagnosed Patients With Hypertension: A Pilot Study.’’ Endothelial dysfunction and inflammation are related to hypertension (HT). Carotid intima–media thickness (cIMT) is associated with inflammation, and high-sensitivity C-reactive protein (hsCRP) is frequently used as an inflammatory marker. In our study, we concluded that cIMT and hsCRP were higher in patients with HT compared to controls. We also reported that endocan is a candidate immunoinflammatory marker that correlated with cIMT and hsCRP. In another study, we reported that patients with Behçet disease (BD) had significantly higher serum levels of endocan. Also, in these patients, serum endocan levels correlated positively with conventional inflammatory markers like hsCRP and erythrocyte sedimentation rate as well as disease activity. Serum levels of endocan were also higher in patients with BD having systemic involvement. In another study, we reported that patients with psoriasis had significantly higher serum levels of endocan. Serum endocan levels also correlated with hsCRP, cIMT, and disease activity in these patients. We investigated the effects of amlodipine and valsartan on endocan levels in newly diagnosed patients with HT. We concluded that amlodipine and valsartan decrease endocan levels in newly diagnosed patients with HT. Aparci et al stated that endocan levels can be affected by vascular risk factors (eg, smoking, alcohol consumption, hypercholesterolemia, and hypothyroidism) and medication (eg, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, and statins). We excluded these factors in our present study. Also, they mentioned that we should also consider other inflammatory markers. We think that hsCRP is satisfactory as a marker of inflammation in a pilot study; it has been widely used in that role. Carotid intima–media thickness also acted as a second marker of inflammation. In any case, Aparci et al extensively document the link between endocan and inflammation in their letter. Finally, we hope that Aparci et al always use a comprehensive battery of tests for all their research projects (including pilot studies) following their recommendation. In conclusion, future randomized controlled studies should investigate the relationship between endocan levels, inflammatory markers, and HT. References

Atherosclerotic Plaque Distribution in the Left Anterior Descending Coronary Artery as Assessed by Intravascular Ultrasound

N studies have demonstrated asymmetric longitudinal and circumferential atherosclerotic plaque distribution along coronary arteries.1,2 In vivo data are limited and have primarily examined the left main artery bifurcation.3,4 In the proximal left anterior descending (LAD) artery, the wall opposite to the circumflex origin is a preferred site of plaque accumulation and is likely secondary to fluid dynamics near the bifurcation.5,6 It has been described that abnormally low or oscillatory shear forces at these sites contribute to atherogenesis.7 Assessment of plaque distribution in the proximal and mid-LAD artery has not been systematically described. Intravascular ultrasound (IVUS) is ideally suited to study distribution patterns of atherosclerotic plaque burden.8 Using a motorized pullback device that withdraws the IVUS catheter at a precisely controlled rate allows accurate mapping of the longitudinal and circumferential plaque patterns. In the present report, in vivo IVUS imaging was employed to examine plaque distribution in the LAD artery in relation to the first septal perforator in patients with mild coronary artery disease (CAD). • • • We analyzed IVUS studies in 50 patients with minimally obstructive CAD ( 50% angiographic diameter stenosis) of the native LAD artery. IVUS imaging was performed in standard fashion using either a 30-MHz, 3.2 or 2.9Fr catheter, or a 40MHz, 2.6Fr device (Cardiovascular Imaging Systems, Sunnyvale, California).9 The IVUS catheter was advanced over a guidewire to a position in the midto distal portion of the LAD artery after the administration of intracoronary nitroglycerin and anticoagulation with intravenous heparin. Motorized pullback at a rate of 0.5 mm/s was performed to the left main ostium with ultrasound images recorded on Super-VHS videotape. A long segment of the LAD artery pullback (20 to 60 seconds) was digitized from videotape into a 640 480-pixel image matrix with an 8-bit gray scale for each patient. The midpoint of the first septal perforator was identified on IVUS and angiographic images, and 7 serial cross-sectional slices were selected (midpoint of septal, 1, 2, and 3 mm proximally and distally) for a total of 350 cross sections (Figure 1). In each cross section, the vessel was divided into two 180° semicircles ipsilateral (septal) and contralateral (antiseptal) to the septal branch. In each semicircle, the external elastic membrane and lumen area were planimetered. Atheroma area (external elastic membrane lumen area) and maximum and minimum intimal thickness were calculated. All results are expressed as mean SD. Comparison of atheroma area and intimal thickness between the septal and antiseptal sides was performed using the paired, 2-tailed Student’s t test. A p value 0.05 was considered statistically significant. Fifty patients with mild coronary atherosclerotic disease of the LAD artery were included in the analysis. In the LAD artery segment adjacent to the first septal branch, mean atheroma area was substantially greater on the septal side than on the antiseptal side (3.44 1.6 vs 2.5 1.5 mm, p 0.0001). Mean intimal thickness on the septal side was also greater than the antiseptal side (1.03 0.48 vs 0.81 0.42 mm, p 0.0001; Table 1). This relation was evident for each of the 7 individual cross sections, and it was remarkably consistent throughout the cohort with 255 of 350 cross sections (73%; Figure 2). A distinctive pattern of longitudinal atheroma distribution was evident. At 3 mm proximal to the septal side, the plaque area on the septal side was much larger than that on the antiseptal side (3.69 1.8 vs 2.36 1.7 mm, p 0.0001). From a more distal position, the differences between septal plaque and the antiseptal side decreased progressively. At 3 mm distal to the septal side, the differences between the septal and antiseptal sides were the smallest (3.00 1.9 vs 2.45 1.5 mm, p 0.0086). Similar findings were noted for maximum atheroma thickness. At 3 mm proximal to the septal artery, the difference in plaque thickness between the septal and antiseptal sides was large (1.10 0.5 vs 0.76 0.4 mm, p 0.0001). The difference was smaller at a site 3 mm distal to the septal artery (0.93 0.5 vs 0.78 0.5 mm, p 0.0051). Figure 3 shows the plaque distribution (mean SD) adjacent to the first septal branch for the overall group. From The Cleveland Clinic Foundation, Cleveland, Ohio; and Yale University School of Medicine, New Haven, Connecticut. Dr. Nissen’s address is: The Cleveland Clinic Foundation, F 15, 9500 Euclid Avenue, Cleveland, Ohio 44195. E-mail: nissens@ccf.org. Manuscript received June 25, 2002; revised manuscript received and accepted October 11, 2002.

The Neutrophil-Lymphocyte Ratio and Inflammation.

Acikgoz commented on our article entitled ‘‘Neutrophillymphocyte ratio (NLR) and carotid-intima media thickness in patients with Behçet disease without cardiovascular involvement.’’ He concluded that although the NLR seems to be a useful inflammatory marker and predictor of the activity of Behçet disease (BD), more research is required to define its exact role in patient management. Behçet disease is a chronic, inflammatory disorder, and endothelial dysfunction (ED) is considered to play a major role in the pathogenesis of vasculitis and thrombosis in BD. Recently, several studies highlighted the relation between ED, BD, and inflammatory markers. Similarly, we reported that patients with BD had significantly higher serum levels of endocan (as a novel endothelial inflammatory marker), and these levels correlated positively with C-reactive protein, erythrocyte sedimentation rate, and BD activity. Serum levels of endocan were higher in patients with systemic involvement. The NLR is a readily available biomarker that conveys information about inflammatory conditions. Furthermore, epidemiological studies reported that chronic inflammation measured by the NLR is related to classic risk factors such as diabetes mellitus, hypertension, metabolic syndrome, obesity, smoking, and elevated cholesterol values. Furthermore, recent evidence reported that the NLR has a significant prognostic value for several conditions in prospective longterm studies. Also, the NLR is influenced by several conditions including medication dehydration, overhydration, diluted blood specimens, and in vitro specimen handling. The NLR may change after medications, and the levels of NLR can be changed by severity of chronic diseases. We agree with Acikgoz that the NLR may also be related to other inflammatory markers and ED. It is also considered that NLR levels positively correlated with carotid intima–media thickness. So, a high NLR may be related to endothelial dysfunction and reflects BD activity. In conclusion, the NLR levels may reflect the severity of diseases with an inflammatory component. Conditions that are related to NLR levels should be kept in mind when NLR levels are interpreted. We need to evaluate this marker for managing and following clinical outcomes in many conditions. We suggest that the NLR should be evaluated together with clinic outcomes such as vascular involvement.

Ankle-Brachial Index and Cardiovascular Outcome.

We read the article ‘‘The Ankle-Brachial Index is Associated With Cardiovascular Complications After Noncardiac Surgery’’ by Carmo et al with interest. They evaluated the role of ankle–brachial index (ABI) as a predictor of cardiovascular (CV) complications in patients with and without an abnormal ABI submitted to noncardiac surgery. An ABI 0.9 indicated a >7-fold chance for the occurrence of the primary outcome. Patients with symptomatic and asymptomatic atherosclerosis or several risk factors have relatively high rates of CV events. Additionally, several studies demonstrated an independent positive association between asymptomatic peripheral artery disease (PAD) and CV events, including stroke, transient ischemic attack, myocardial infarction, and death among patients with previous stroke. Serena et al analyzed the adjusted predictive capacity of the ABI together with additional markers of atherothrombotic disease as predictors of CV events. In the ARTICO stroke population, symptomatic PAD and particularly the association of both symptomatic PAD and ABI 0.9 with internal carotid artery stenosis >50% were independently associated with a 3.72 and 4.39 times increased risk of new vascular events. The ABI is a relatively simple, easy, noninvasive, and inexpensive test, and it is >90% sensitive and specific compared with angiography, the gold standard. Although the ABI provides several benefits, it also has limitations. For example, 10% of the general population have a congenital absence of the dorsalis pedis or posterior tibial artery meaning that ABI would not be accurate. In conclusion, Carmo et al describe the ABI as a predictor of CV complications in patients with noncardiac surgery. This relationship needs to be evaluated in large-scale prospective randomized clinical trials.

Percutaneous transcatheter closure of atrial and ventricular septal defect in the same session

A 23-year-old man was admitted to our outpatient clinic with the complaint of exertional dyspnea and palpitation. His medical history was unremarkable. Electrocardiography showed a sinus rhythm with a complete right bundle branch block. Two-dimensional transthoracic echocardiography revealed moderately dilated right heart chambers and defects at the interatrial and interventricular septum. The calculated Qp/Qs was 2.5. Two-dimensional transesophageal echocardiography (2D TEE) midesophageal four-chamber view confirmed secundum atrial septal defect (ASD) and ventricular septal defect (VSD) (Figure A, B, Video 1*). For further evaluation of this pathology, we applied three-dimensional transesophageal echocardiography (3D TEE). 3D color Doppler TEE demonstrated the defect at the interventricular septum (Figure C). We decided to close these defects percutaneously because he was symptomatic, and Qp/Qs was higher than normal values. We firstly closed the ASD with a septal occluder device. Then, we performed left ventriculography, which showed the tunnel-like VSD (Figure D, thin arrow), and closed the VSD with a septal occluder device (Figure E). 2D TEE midesophageal four-chamber view (Figure F and Video 2*) and 3D full-volume modality after cropping (Figure G and Video 3*) revealed the ASD and VSD devices. 2D TEE can provide useful information by monitoring transcatheter closure, while 3D TEE enhanced our ability to better define the atrial and ventricular septal anatomy and to assess the true size and morphology of the defect, enabling easier catheter closure. We herein report percutaneous transcatheter closure of ASD and VSD in the same session using multimodality imaging. To the best of our knowledge, this is the first such case in the literature. 314