Tulin Yalta

Copeptin and cardiovascular disease: a review of a novel neurohormone.

Neurohormones (NHs) in the cascade of the arginine vasopressin (AVP) system have drawn particular attention in the recent years. Copeptin, the C-terminal portion of provasopressin, is a novel NH of the AVP system, and is known to be co-released with AVP from hypothalamus (neurohypophysis). As a surrogate marker of the AVP system, copeptin has gradually replaced AVP in several clinical studies largely due to its structural and methodological advantages. Copeptin has been regarded as a marker of non-specific stress response, and has also been suggested to have clinical implications in a variety of non-cardiovascular (pneumonia, sepsis, etc.) and cardiovascular conditions (heart failure and acute coronary syndromes (ACSs, etc.)). However, current data on relation of copeptin with other cardiovascular conditions ( arrhythmias, etc.) are still insufficient. The present review primarily focuses on general features of copeptin, its general clinical implications, and specifically aims to cover its potential clinical value in a variety of cardiovascular conditions.

Copeptin (C-terminal provasopressin): A promising marker of arrhythmogenesis in arrhythmia prone subjects?

Neurohormones have drawn particular attention in the recent years possiblyduetotheirpotentialdiagnosticandprognosticvalues inavarietyof clinical conditions includingcongestiveheart failure(CHF), acutemyocardial infarction (AMI), etc. Among neurohormones, arginine vasopressin (AVP) has been known to be secreted by hypothalamus in response to hypovolemia and increased plasma osmolality [1], and was also demonstrated to be a marker of the presence and severity of CHF [2]. However as described below, the potential association between AVP system and arrhythmogenesis may also confer some important therapeutic and prognostic implications in arrhthmia-prone patients. In the recent years, due to the instability and rapid clerance [1], the clinical utility of AVP has beengraduallyabandonedtosomedegree, andcopeptin(CP), anothernovel neurohormone of the AVP system, has come into use in the clinical practice. CP, the C-terminal portion of provasopressin [1], is co-released with AVP from hypothalamus. CP is structurally more stable, and hence may mirror the stable levels of AVP associated with the severity of the related disease [1]. CP was recently demonstrated to be a strong predictor of mortality and morbidity in patients suffering heart failure after an AMI [1]. In another study [3], CP was found to be associated with left ventricular dysfunction (inverse correlation between copeptin levels and left ventricular ejection fraction (LVEF)) in the early (at discharge) and late stages (on follow-up) of AMI indicating that hyperactivation of the AVPsystemseems tobea contributor (via inducing remodelling) and/or a consequence in the process of heart failure development. However, as an absolute clinical implication inCHF, substantial levels of CPmay indirectly denotepoor systemicperfusionassociatedwithdepressed left ventricular systolic function (a notion consistent with a previous study that demonstrated a negative correlation between AVP and cardiac index [2]). CHF is a well known trigger for malign ventricular arrhythmias through various mechanisms including structural alterations of myocardium, increased myocardial wall tension, adrenergic activation, enhanced effects of the AVP system on the heart, etc. AVP (co-secreted with CP) was suggested to induce protein synthesis, cardiac hypertrophy [4] and collagen synthesis in cardiac fibroblasts [5] in rats that may not only induce myocardial remodelling but may also create an arrhythmogenic substrate for malign ventricular arrhythmias indicating direct arrhythmogenic effects of AVP on myocardium in patients with CHF. It may be suggested that the association between CP levels and arrhythmogenesis may be dependent on left ventricular function, to some extent. However, this association may still persist even after adjustment for parameters of left ventricular function (LVEF, etc.) suggesting CP as an arrhythmogenic marker in arrhythmia-prone patients without heart failure as well. In the absence of heart failure, CP may still remain associated with arrhythmogenesis through various potentialmechanisms: CPwas found to be associatedwith the individual stress level [6]. In a very recently published study, CP was reported to have an additional diagnostic value in AMI (for rapid rule out) as an endogenous stress marker [7]. Hyperactivation of the adrenergic system is generally suggested to trigger malign ventricular arrhythmias and sudden cardiac death (SCD) in arrhythmia-prone subjects [8], and iswell known to be associated with the endogenous stress level. Therefore, CP may be regarded as a promising biochemical marker of arrhythmogenesis in arrhytmia-prone patients with and without heart failure. It may be suggested that besides conventional indices of arrhythmogenesis (QT dispersion, T wave alternance (TWA), heart rate variability (HRV), etc.), clinicians are in need of novel biochemicalmarkers thatmay rapidly and reliably predict the risk for arrhythmogenesis and arrhythmic mortality in arrhythmia-prone patients. CP, the novel and promising marker with strong predictive values, may help predict arrhythmia risk, and may help determine the therapeutic strategy in these patients. However, future large scale studies particularly focusing on the link between arrhythmogenesis and CP in arrhythmia-prone subjects are still warranted to confirm the clinical utility of CP in these patients. The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology [9].

The histopathological comparison of L-carnitine with amifostine for protective efficacy on radiation-induced acute small intestinal toxicity

BACKGROUND The aim of the study was to compare the protective efficacy of l-carnitine (LC) to amifostine on radiation-induced acute small intestine damage. MATERIALS AND METHODS Thirty, 4-week-old Wistar albino rats were randomly assigned to four groups - Group 1: control (CONT, n = 6), Group 2: irradiation alone (RT, n = 8), Group 3: amifostine plus irradiation (AMI+RT, n = 8), and Group 4: l-Carnitine plus irradiation (LC+RT, n = 8). The rats in all groups were irradiated individually with a single dose of 20 Gy to the total abdomen, except those in CONT. LC (300 mg/kg) or amifostine (200 mg/kg) was used 30 min before irradiation. Histopathological analysis of small intestine was carried out after euthanasia. RESULTS Pretreatment with amifostine reduced the radiation-induced acute degenerative damage (P = 0.009) compared to the RT group. Pretreatment with LC did not obtain any significant difference compared to the RT group. The vascular damage significantly reduced in both of the AMI+RT (P = 0.003) and LC+RT group (P = 0.029) compared to the RT group. The overall damage score was significantly lower in the AMI+RT group than the RT group (P = 0.009). There was not any significant difference between the LC+RT and RT group. CONCLUSIONS Amifostine has a marked radioprotective effect against all histopathological changes on small intestinal tissue while LC has limited effects which are mainly on vascular structure.

Neuropeptide Y-induced coronary microvascular dysfunction: A significant contributor to the adverse outcomes in stress cardiomyopathy?

⁎ Corresponding author. E-mail address: kyalta@gmail.com (K. Yalta). In their recently published article, Szardien et al. reported a 78year-old female patient who had suffered stress cardiomyopathy (SCM) accompanied by increased serum levels of neuropeptide Y (NPY) [1]. We agree with the authors that increased serum NPY levels may contribute to myocardial contractile dysfunction and hence may also be regarded as a prognostic marker in patients with SCM [1]. However, in the setting of SCM with substantial NPY levels, NPYinduced coronary microvascular dysfunction, as described below, may also contribute significantly to the adverse clinical outcomes including ischemic malign arrhythmias, etc. Transient wall motion abnormalities including left ventricular apical ballooning have been regarded as one of the main characteristics of SCM [2]. Catecholamine-induced myocardial dysfunction, coronary microvascular dysfunction and coronary spasm etc have been suggested as potential etiologies of this entity. Recently, NPY has also been suggested to contribute to myocardial dysfunction in SCM indicating its potential prognostic value [1]. Notwithstanding the generally accepted benign nature of SCM, relatively high rates of malign ventricular arrhythmias and mortality were reported in some patient series [3]. Even though the exact mechanisms leading to adverse events (malign ventricular arrhythmia, etc.) in SCM is still largely unknown, severe coronary microvascular dysfunction may be considered as a potential trigger in some patients. Endothelial dysfunction [4] and increased serum NPY (a vasoconstrictor hormone) [5] levels are well known to play the central role in the pathogenesis of coronary microvascular syndromes. Among these syndromes, coronary syndrome Y (characterized by coronary slow flow (CSF)) is associated with enhanced coronary resistance, and may present with the clinical picture of acute coronary syndrome (ACS) along with an increased proclivity to cardiac arrhythmias [4]. Similarly, in the setting of SCM, severe and transient coronary microvascular dysfunction induced by excessive levels of NPY may be associated with adverse clinical outcomes including ischemic malign arrhythmic events and sudden cardiac death (SCD), etc. (regardless of the presence of severe left ventricular systolic dysfunction). Therefore, besides clinical presentation, SCM with excessive NPY levels may resemble ACSs in terms of prognostic features. Even though, the case reported by Szardien et al. [1] did not suffer any SCM-related adverse event, substantial levels of NPY might indicate the possibility of severe coronary microvascular dysfunction (with or without CSF) in this case. It may be suggested that NPY-induced severe coronary microvascular dysfunction may account for life-threatening ischemic adverse events including malign ventricular arrhythmias in SCM patients with substantial levels of NPY during the disease course. Therefore, these patients may be regarded as a subgroup with potentially worse prognosis due to severe coronary microvascular dysfunction indicating the need for close monitoring and aggressive management as in the event of ACSs. Besides conventional therapeutic strategies including management of heart failure, arrhythmias and anticoagulation, etc., targeting enhancement of coronary blood flow along with the use of intensive anti-ischemic regimens may be of clinical value during the disease course and may help improve prognosis in SCM patients with substantial serum levels of NPY. The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology [6].

Systemic Inflammation and Arrhythmogenesis: A Review of Mechanistic and Clinical Perspectives

In the recent decades, systemic inflammation, as a clinical phenomenon, has been the focus of extensive research particularly with regard to its potential association with a variety of cardiovascular diseases including atherogenesis and acute coronary syndromes. Within this context, there also exists a potential link between systemic inflammation and cardiac arrhythmogenesis in various aspects. Accordingly, systemic inflammation response as measured with inflammation markers (cytokines, etc) has been investigated in the setting of well-known cardiac arrhythmias including atrial fibrillation and ventricular tachycardia. Based on current literature, clinical utility of these markers might potentially yield important prognostic implications in the setting of certain arrhythmogenic conditions. On the other hand, there exists limited data regarding therapeutic implications including clinical benefit of primary anti-inflammatory agents (corticosteroids, colchicine, etc) in the setting of arrhythmia management. The present review primarily aims to discuss potential triggers and fundamental mechanisms of inflammation-related arrhythmias along with a particular emphasis on clinical implications of systemic inflammation in the setting of cardiac arrhythmogenesis.

Evaluation of Cardiovascular Risk Factors in Women with Uterine Leimyoma: Is There a Link with Atherosclerosis?

OBJECTIVE Both uterine leimyoma (UL) and cardiovascular disease are public health problems affecting women at different age ranges. Smoking, obesity, and hypertension have been shown to be associated with UL in different random studies. However cardiovascular risk factors have not been evaluated systematically in patients with UL. Accordingly, we aimed to evaluate the cardiovascular risk factors and their relation with the presence of UL. MATERIAL AND METHODS One hundred and eighty nine patients with the pathological diagnosis of UL and one hundred and eighty nine age matched control subjects without UL were retrospectively included in the study from our data base of the pathology and gynecology departments. Controls were patients with intact uteri who had visited the same physicians for a routine checkup that included a pelvic examination and uterine sonogram and without mention of physical findings consistent with UL. The following clinical and demographic parameters were recorded; age, sex, hypertension, diabetes mellitus, and hypercholesterolemia. Current cigarette smoking was defined as active smoking within the past 12 months. RESULTS Comparison of cardiovascular risk factors between with and without UL revealed that the presence of hypertension (80 (42.3%) vs 53 (28%) p=0.004) diabetes mellitus (33 (17.4%) vs. 16 (8.4%) p=0.009), smoking (31 (16.4%) vs. 11 (5.8%) p=0.001), were significantly higher in patients with UL than in control subjects. The mean-age and presence of hyperlipidemia were comparable between the two groups. Logistic regression analysis revealed an independent and positive association of UL with the presence of hypertension (odds ratio 2.02 CI: 1.25-3.27 p=0.004), diabetes mellitus (odds ratio 2.43 CI: 1.23-4.79 p=0.010), and smoking status (odds ratio 3.46 CI: 1.65-7.22 p=0.001). CONCLUSION We have shown that major cardiovascular risk factors namely, hypertension, diabetes mellitus and smoking are significantly and independently associated with UL. Our findings highlight the possible association of UL with atherosclerosis.

Protective effect of everolimus on renal ischemia reperfusion injury in rats.

The aim of this study was to determine the effect of everolimus and tacrolimus pretreatments on renal morphology and function in a rat ischemia reperfusion (I/R) model. Twenty-eight male Sprague-Dawley rats were randomly assigned to saline + sham operation, saline + I/R (IR), tacrolimus + I/R (TRL + I/R) and everolimus + I/R (ERL + I/R) groups. Saline and active treatments were administered intraperitoneally for seven consecutive days before the surgery. The suprarenal aorta was clamped to achieve warm ischemia, except in the sham group. Right nephrectomy was performed in all animals and histology was examined. Renal function was assessed on post-operative Day 7 by Tc-99m dimercaptosuccinic acid (DMSA) scintigraphy, glomerular filtration rate (GFR) and serum biochemistry. Both everolimus and tacrolimus preserved serum creatinine and blood urea nitrogen levels, but only everolimus preserved GFR (0.74 ± 0.36, 1.20 ± 0.37 and 2.24 ± 0.32 mL/min for I/R, TRL + I/R and ERL + I/R, respectively, P < 0.001). %ID values for sham, I/R, TRL + I/R and ERL + I/R were 55 ± 3, 47 ± 4, 45 ± 6 and 62 ± 7 (P < 0.001). On histologic evaluation, ERL + I/R showed less tubular damage and necrosis than I/R, as well as TRL + I/R. Within the confines of this rat warm ischemia model, everolimus pre-treatment was useful in preserving renal function following I/R injury. The possibility of using everolimus as a pre-conditioning agent for I/R injury in kidney transplantation should be further explored.

Combined effects of tauroursodeoxycholic Acid and glutamine on bacterial translocation in obstructive jaundiced rats

BACKGROUND Bacterial Translocation is believed to be an important factor on mortality and morbidity in Obstructive Jaundiced. AIMS We investigated the probable or estimated positive effects of tauroursodeoxycholic acid, which has antibacterial and regulatory effects on intestinal flora, together with glutamine on BT in an experimental obstructive jaundiced rat model. STUDY DESIGN Animal experimentation. METHODS Forty adult, male, Sprague Dawley rats were used in this study. Animals were randomised and divided into five groups of eight each: sham (Sh); control (common bile duct ligation, CBDL); and supplementation groups administered tauroursodeoxycholic acid (CBDL+T), glutamine (CBDL+G), or tauroursodeoxycholic acid plus glutamine (CBDL+TG). Blood and liver, spleen, MLN, and ileal samples were taken via laparotomy under sterile conditions for investigation of bacterial translocation and intestinal mucosal integrity and hepatic function tests on the tenth postoperative day. RESULTS There were statistically significant differences in BT rates in all samples except the spleen of the CBDL+TG group compared with the CBDL group (p=0.041, p=0.026, and p=0.041, respectively). CONCLUSION It is essential to protect hepatic functions besides maintaining intestinal mucosal integrity in the active struggle against BT occurring in obstructive jaundice. The positive effect on intestinal mucosal integrity can be increased if glutamine is used with tauroursodeoxycholic acid, which also has hepatoprotective and immunomodulatory features.

The effects of apelin on mesenteric ischemia and reperfusion damage in an experimental rat model.

OBJECTIVE Intestinal ischemia-reperfusion (I/R) injury is associated with high morbidity and mortality rates. There is ongoing research to find an effective preventive or treatment agent. We aimed to evaluate the effects of apelin 13 (AP) on intestinal I/R injury in a rat model. MATERIAL AND METHODS Twenty-four male Sprague-Dawley rats aged 6-8 weeks and weighing 280±20 g were equally divided into three groups (control, I/R and I/R+AP). The control group underwent superior mesenteric artery (SMA) mobilization alone without any clamping. In the I/R and I/R+AP groups, an atraumatic microvascular bulldog clamp was placed across the SMA at its point of origin from the aorta. In the I/R+AP group, 2 μg/kg/d apelin was administered intraperitoneally. After 60 minutes of ischemia, relaparotomy was performed to remove the microvascular clamp on the SMA for 3 hours of reperfusion. After 3 hours, tissue samples were obtained for biochemical [malondialdehyde (MDA) and glutathione (GSH) levels] and histopathological analyses. RESULTS MDA levels were significantly higher in the I/R group compared to the control group. Although MDA levels were lower in the I/R+AP group compared tothe I/R group, the difference was not statistically significant. There was also no significant difference between the I/R+AP and I/R groups regarding GSH levels. The median histopathological grade was significantly lower in the I/R+AP group compared to the I/R group (p=0.001). CONCLUSION Apelin appeared to have a positive effect on oxidative injury; this did not reach statistical significance. Thus, the role of apelin and associated findings in the initial treatment of intestinal ischemia needs further large-scale animal studies before human use.

Serum ferritin: A potential determinant of myocardial ischemic burden in the setting of ischemic conditions?

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