Everolimus- and zotarolimus-eluting stents for bare metal stent in-stent restenosis treatment: a prospective study.

BACKGROUND: Treatment of in-stent restenosis (ISR) is a challenging clinical problem. Recent studies have verified the safety and efficacy of first-generation DES for the treatment of ISR. The safety and effectiveness of new-generation drug-eluting stents (nDES) for ISR has not been previously investigated. The aim of the present study was to prospectively evaluate the clinical outcomes after treatment with nDES implantation in patients with bare metal stent (BMS) ISR. METHODS: Consecutive patients with ISR after BMS implantation were included. Primary end-point was a major adverse cardiac event (MACE), defined as death, myocardial infarction (MI), or target vessel revascularization (TVR). The incidence of stent thrombosis was also evaluated. RESULTS: A total of 46 consecutive patients were enrolled for the treatment of ISR, 23 patients from ZES and 23 from EES group. There were two (8.7%) cases of TVR in ZES cohort due to proliferative ISR at 6 and 7 months after DES implantation, and none in EES. One (4.3%) patient underwent percutaneous coronary intervention and the other (4.3%) was treated surgically. Neither acute nor subacute thrombosis was observed during the 13.3+/-6.3 months follow-up period. In all other patients, stress test was negative for ischemia at 6 months. CONCLUSIONS: In this prospective study, we showed that direct nDES implantation is highly effective for ISR and seems to be a promising management for the treatment of ISR.

Serum uric acid levels correlate with left atrial function and systolic right ventricular function in patients with newly diagnosed heart failure: the hellenic heart failure study.

The authors sought to investigate whether serum uric acid levels are associated with systolic left and right ventricular function, as well as left atrial function in patients with newly diagnosed heart failure. The authors enrolled 106 consecutive patients (mean age 65+/-13 years). Echocardiographic and biochemical assessment was performed during the third day of hospitalization. Pulsed tissue Doppler imaging of the systolic function of mitral and tricuspid annulus was characterized by the systolic waves (Smv and Stv, respectively), expressed in cm/s, and the left atrial function by the Amv wave. Left atrial kinetics was calculated using an equation. Serum uric acid levels were inversely correlated with Stv (P=.005) and left atrial kinetics (P=.05), after controlling for potential confounders. Uric acid levels appear to be correlated with more impaired right ventricular systolic function and decreased left atrial work in patients with heart failure.

Effects of insulin dependence on inflammatory process, thrombotic mechanisms and endothelial function, in patients with type 2 diabetes mellitus and coronary atherosclerosis.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is characterized by endothelial dysfunction, increased thrombogenicity and abnormal inflammatory response. HYPOTHESIS: We hypothesizsed that insulin dependence/exogenous insulin administration may affect thrombotic/inflammatory status and endothelial function in patients with T2DM and coronary artery disease (CAD). METHODS: Fifty-five patients with T2DM + CAD (26 insulin-treated (INS) and 29 under oral biguanide + sulphonylurea (TABL)) were recruited. Endothelial function was assessed by gauge-strain plethysmography, and serum levels of inflammatory and thrombotic markers were determined by enzyme linked immunosorbent assay. RESULTS: There was no significant difference in endothelium-dependent dilation (EDD) between the study groups, while EDD was correlated with fasting glucose levels in both INS (r = - 0.776, p = 0.0001) and TABL (r = - 0.702, p = 0.0001). Patients in INS group had higher levels of interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-alpha), monocyte chemoattractant protein (MCP-1) and vascular cell adhesion molecule (sVCAM-1), compared to TABL. However, TNF-alpha was negatively correlated with protein C (PrtC) only in INS (r = - 0.726, p = 0.01) but not in TABL group (r = - 0.066, p = 0.738). Similarly, sVCAM-1 was correlated with PrtC only among INS patients (r = - 0.451, p = 0.046) but not in TABL (r = 0.069, p = 0.727). In multivariate analysis, insulin dependence was a predictor of IL-6, TNF-alpha, MCP-1 and sVCAM-1 levels independently from the patients' demographic characteristics, the angiographic extend of CAD or the duration of diabetes. CONCLUSIONS: Insulin treatment in patients with type 2 diabetes mellitus affects the expression of inflammatory cytokines and subsequently modifies the thrombotic mechanisms in patients with coronary atherosclerosis, independently from the duration of diabetes and the extend of coronary artery disease.

Potential role of endothelial progenitor cells in the pathophysiology of heart failure: clinical implications and perspectives.

Endothelial dysfunction is thought to play a major role in the development and clinical complications of heart failure. Endothelial progenitor cells (EPCs) have been shown to provide an endogenous repair mechanism to counteract detrimental risk factor-induced effects and replace dysfunctional endothelium. The number and in vitro function of EPCs is altered in patients with heart failure, as a result of its pathophysiological mechanisms. EPCs could represent a substitutional marker to guide preventive or therapeutic interventions in this disease. Enhancing the number and functional capacity of EPCs with targeted interventions may elicit functional improvement in individuals with heart failure. However, the exact role of EPCs in heart failure and their potential therapeutic implications still remain to be elucidated.

Genetic polymorphisms G894T on the eNOS gene is associated with endothelial function and vWF levels in premature myocardial infarction survivors.

BACKGROUND: Genetic polymorphism G894T on endothelial nitric oxide synthase (eNOS) gene has been associated with endothelial dysfunction in young smokers, but its role in the pathogenesis of MI is obscure. We examined the effect of G894T polymorphism on endothelial function, on markers of endothelial cells injury and activation such as von Willebrand factor (vWF) and on serum levels of proinflammatory cytokines such as interleukins 6 (IL-6) and 1b (IL-1b), in young myocardial infarction (MI) survivors. METHODS: The study population consisted of 56 patients with a history of premature MI. The forearm blood flow (FBF) was measured by using strain-gauge plethysmography during reactive hyperemia and after sublingual administration of nitroglycerin. G894T polymorphism was determined by polymerase chain reaction (PCR), while plasma vWF and serum IL1b and IL-6 levels were determined with ELISA. RESULTS: There was no significant difference in resting FBF and in the responses to nitroglycerin between the genotypes. However, the presence of T allele (GT+TT, n=35) was associated with decreased FBF during reactive hyperemia (10.23+/-0.70 ml/100ml tissue/min) and decreased forearm vasodilatory response to reactive hyperemia (54.28+/-4.81%) compared to GG (13.82+/-0.92 ml/100 ml tissue/min and 83.92+/-9.89% respectively, p<0.01 for both). Carriers of the T allele had also higher levels of vWF (79.66+/-5.56%) compared to GG (60.94+/-5.27% p<0.05). However, no significant difference was observed in IL-1b and IL-6 serum levels between the genotypes (p=ns for both). CONCLUSIONS: The presence of 894T allele on eNOS gene is associated with impaired endothelial function and higher levels of von Willebrand factor in relatively young patients with myocardial infarction. This finding implies that genetic polymorphism G894T on eNOS may affect endothelial function in patients with a history of premature myocardial infarction.

Effects of combined administration of low dose atorvastatin and vitamin E on inflammatory markers and endothelial function in patients with heart failure.

BACKGROUND: Heart failure has been associated with impaired endothelial function, increased inflammatory process and elevated oxidative stress status. Both statins and vitamin E separately improve endothelial function in patients with hypercholesterolemia and/or advanced atherosclerosis. AIM: To evaluate the effect of atorvastatin alone or in combination with vitamin E on endothelial function and serum levels of interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-alpha) and vascular cells adhesion molecule (sVCAM-1) in patients with ischemic heart failure. METHODS: Thirty-eight male patients with ischemic cardiomyopathy were randomly divided into three groups and received either atorvastatin 10 mg/day (n = 14), a combination of atorvastatin 10 mg/day plus vitamin E 400 IU/day (n = 12), or no statin or antioxidant treatment (n=12, controls) for 4 weeks. Forearm blood flow (FBF) was measured using venous occlusion strain-gauge plethysmography. Forearm vasodilatory response to reactive hyperemia (RH%) or to nitrate (NTG%) was defined as the percent change of FBF from rest to the maximum flow during reactive hyperemia or after nitrate administration, respectively. RESULTS: RH% was significantly improved in both the atorvastatin-treated (p < 0.01) and atorvastatin plus vitamin E groups (p < 0.05), but the increase was significantly higher in the atorvastatin-treated group (p < 0.05). Serum levels of IL-6, TNF-alpha and sVCAM-1 were decreased in the atorvastatin-treated group (p < 0.05 for all), but remained unaffected in the other two groups (p = NS for all). CONCLUSIONS: Low dose atorvastatin treatment improves endothelial function and reduces the expression of proinflammatory cytokines and adhesion molecules in patients with ischemic heart failure, an effect partly depressed by vitamin E.

Effects of combined administration of vitamins C and E on reactive hyperemia and inflammatory process in chronic smokers.

Purpose of this study was to investigate the effect of combined administration of antioxidant vitamins C and E on endothelial function and serum levels of inflammatory markers such as tumor necrosis factor alpha (TNF-alpha), interleukines 1b (IL-1b) and 6 (IL-6), vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1) and E-selectin in chronic smokers. Forty-three smokers were randomly divided into four groups receiving vitamin C 2 g/day (group A), vitamin C 2 g/day plus vitamin E 400 IU/day (group B), vitamin C 2 g/day plus vitamin E 800 IU/day (group C) or no antioxidant treatment (group D), for 4 weeks. Forearm blood flow (FBF) was measured using venous occlusion strain gauge plethysmography. Forearm vasodilatory response to reactive hyperemia (RH%) was expressed as the percentage change from baseline to post reactive hyperemia blood flow. RH% was significantly increased in groups B (P<0.05) and C (P<0.01), but remained unaffected in groups A and D. Serum levels of IL-1b, IL-6, sVCAM-1 and sICAM-1 were significantly reduced in group C (P<0.05, respectively), but remained unaffected in groups A, B and D. Thus, short term administration of vitamins C (2 g/day) and E (800 IU/day) reduces serum levels of IL-1b, IL-6, sVCAM-1 and sICAM-1, and improves forearm vasodilatory response to reactive hyperemia in healthy young smokers, while monotherapy with vitamin C alone is ineffective.

Effects of antioxidant vitamins C and E on endothelial function and thrombosis/fibrinolysis system in smokers.

Smoking is associated with endothelial dysfunction and abnormalities in thrombosis/fibrinolysis system, possibly through increased oxidative stress. In this study we investigated the effect of combined antioxidant treatment with vitamins C and E on endothelial function and plasma levels of plasminogen activator inhibitor (PAI-1), von Willebrand factor (vWF), tissue plasminogen activator (tPA) and factor VII (fVII), in smokers. Forty-one healthy smokers were randomly divided into 4 groups receiving vitamin C 2g/day (group A), vitamin C 2g/day plus vitamin E 400 IU/day (group B), vitamin C 2g/day plus vitamin E 800 IU/day (group C) or no antioxidants (controls, group D), for 4 weeks. Forearm blood flow was measured using venous occlusion strain-gauge plethysmography. Forearm vasodilatory response to reactive hyperemia (RH%) or to sublingual nitroglycerin administration (NTG%) were considered as indexes of endothelium dependent or independent dilation respectively. After treatment, RH% was increased only in groups B (p <0.05) and C (p <0.001) but not in groups A and D. Plasma levels of PAI-1 and vWF were decreased only in group C (p <0.05 for both), while PAI-1/tPA ratio was significantly decreased in both groups B and C (p <0.05 for both). NTG% and plasma levels of tPA and fVII remained invariable in all groups. In conclusion, combined administration of vitamin C and vitamin E at high dosages, improved endothelial function and decreased plasma levels of PAI-1, vWF and PAI-1/tPA ratio in chronic smokers.

Combined effects of smoking and hypercholesterolemia on inflammatory process, thrombosis/fibrinolysis system, and forearm hyperemic response.

The combined effects of smoking and hypercholesterolemia on the inflammatory process, the thrombosis/fibrinolysis system, and forearm hyperemic response were investigated. It was shown that smokers with hypercholesterolemia (n = 25) had a reduced and delayed forearm hyperemic response compared with healthy smokers (n = 24), patients with hypercholesterolemia (n = 26), and healthy controls (n = 75; p <0.01 for all). This phenomenon was associated with a respective increase in the inflammatory process and changes in the thrombosis/fibrinolysis system.

Endothelial function and proinflammatory cytokines in patients with ischemic heart disease and dilated cardiomyopathy.

BACKGROUND: Proinflammatory cytokines such as tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6) are important mediators of immune response, associated with endothelial dysfunction in patients with coronary artery disease (CAD) or heart failure. We compared endothelial function and levels of IL-6 and TNF-alpha between patients with ischemic heart failure, dilated cardiomyopathy, CAD and healthy controls. METHODS: The population consisted of 20 patients with dilated cardiomyopathy, 48 patients with ischemic cardiomyopathy, 26 patients with CAD and normal left ventricle function and 14 healthy controls. Forearm blood flow was measured using venous occlusion strain gauge plethysmography. Forearm vasodilatory response to reactive hyperemia (RH%) or to nitrate were considered as indexes of endothelium-dependent and endothelium-independent dilation, respectively. RESULTS: Levels of IL-6 were significantly higher in ischemic cardiomyopathy compared to CAD patients (P<0.05) or controls (P<0.05) and in patients with dilated cardiomyopathy compared to controls (P<0.05). TNF-alpha levels were significantly higher in both groups with ischemic or dilated cardiomyopathy compared to CAD (P<0.05) or controls (P<0.05). RH% was significantly lower in ischemic and dilated cardiomyopathy compared to CAD (P<0.05) or controls (P<0.001) and higher in dilated than ischemic cardiomyopathy (P<0.05). CONCLUSIONS: Impaired endothelial function and increased inflammatory process were found in both types of heart failure. A greater endothelial dysfunction was observed in patients with ischemic heart failure compared to those with dilated cardiomyopathy, implying that the underlying atherosclerosis may participate in this process.

Effects of lipids on thrombotic mechanisms in atherosclerosis.

Cholesterol lowering therapy markedly reduces the frequency of subsequent cardiovascular events and is associated with a modest degree of angiographic regression of atherosclerotic lesions. There is a strong association between lipids and fibrinogen, plasminogen activator-1, and activated factor VII levels. Low density lipoprotein may be thrombogenic whereas high density lipoprotein protects against thrombosis. Lipoprotein (a) may affect atherosclerosis and thrombosis mainly by binding to fibrin and attenuating the fibrin-enhanced plasminogen activation. Tissue factor-complex initiates coagulation by activating factor X and factor IX leading in the presence of calcium to the generation of thrombin. Lipid lowering treatment with statins stabilizes atheromatous plaque and has antithrombotic effects. Therefore there are links between lipids and the haemostatic mechanisms which affect atherosclerotic, vasomotor and thrombotic components of ischemic heart disease.

Basic fibroblast growth factor changes in response to coronary angioplasty in patients with stable angina.

Basic fibroblast growth factor (bFGF) has been implicated in the pathogenesis of coronary atherosclerosis and in angiogenesis. We assessed the changes in serum bFGF before, immediately after, and 6 months after coronary angioplasty (PTCA). Using the ELISA methods we measured plasma bFGF in 28 patients who underwent PTCA, in 20 patients with coronary artery disease who underwent elective coronary angiography and in 28 healthy subjects. Before PTCA and coronary angiography, bFGF plasma levels were similar in both patient groups (4.4+/-1.0 vs. 3.3+/-0.5 pg/ml), but were significantly higher compared with those of the control group (0.8+/-0.1 pg/ml, P<0.05). By 24 h, 3 months and 6 months after PTCA, bFGF levels had decreased significantly in the PTCA group (3.2+/-0.6, 1.7+/-0.3 and 2.7+/-0.6 pg/ml, respectively, P<0.05). In conclusion, these findings show that bFGF levels are elevated in patients with coronary artery disease. Following PTCA, bFGF levels decreased significantly and remained stable for 6 months after the procedure. Thus, bFGF level may change in response to PTCA in patients with coronary artery disease and stable angina.

Effects of smoking on nitric oxide synthesis in epicardial normal and atheromatous coronary arteries.

The effects of an intracoronary infusion of N(G)-monomethyl-L-arginine (LNMMA) followed by intracoronary administration of nitroglycerin in non-stenotic proximal and distal coronary segments were studied in 11 patients with coronary artery disease and in 19 subjects with "normal arteriograms". In normal subjects, LNMMA induced significant constriction (p<0.01) of proximal and distal vessels in non-smokers and smokers. In normal non-smokers, the reduction in coronary luminal diameter of proximal segments was significantly greater compared to normal smokers (p<0.05). In patients with coronary artery disease, LNMMA induced significant constriction of proximal and distal vessels in smokers, and only distal constriction in non-smokers (p<0.01). The reduction in coronary luminal diameter of the distal segments in normal smokers, and in both groups in patients with coronary artery disease was significantly greater compared with proximal segments (p<0.05). Therefore, the difference in vasomotor response to LNMMA in relation to smoking is localised to the proximal coronary segments.

Antioxidant treatment and endothelial dysfunction: is it time for flavonoids?

Endothelial dysfunction represents an imbalance between vasodilatory and vasoconstrictory molecules secreted by endothelium. Oxidative stress is a major factor leading to endothelial dysfunction with significant prognostic implications for cardiovascular events. The generation of reactive oxygen species is strongly related to various oxidase enzymes such as xanthine oxidase, uncoupled endothelial nitric oxide synthase, cyclooxygenase, glucose oxidase, lipooxygenase, nicotinamide-adenine dinucleotide phosphate oxidase and to mitochondrial electron transport mechanisms. Several pharmaceutical agents exert effects beyond their principal role, such as anti-inflammatory and antioxidant, while the reports on antioxidant vitamins remain controversial especially those based on large scale studies. Moreover, there are studies on other agents already patented, but these are not well evaluated. Recently, there is growing interest in the role of dietary flavonoids and their potential to improve endothelial function by modifying oxidative stress status. Flavonoids are important components of 'functional foods', with beneficial effects on cardiovascular health, mainly due to their antioxidant activity. However, the vascular-protective role of flavonoids and especially their antioxidant properties are still under investigation.

Prognostic role of miRNAs in coronary artery disease.

The increasing prevalence of coronary artery disease (CAD) as well as its' monitoring remain crucial problems and fields of long debate. Thus, several circulating biomarkers have been found during the last decade and examined in terms of their potential to assist in the prognosis of CAD. Of great interest, are small non-coding RNAs (microRNAs or miRNAS or miRs), due to their association with many aspects of CAD. microRNAs circulate in the bloodstream, while they exist in tissues and affect plaque initiation and progression. In addition, they have been found to contribute to the pathophysiology of CAD and to the CAD-related manifestations such as myocardial infarction, heart failure and cardiac arrhythmias. Therefore, evaluating the role of these molecules may be of great importance in the understanding of atherogenesis providing new evidence for diagnosis and prognosis of CAD.

Effect of statin pretreatment on the outcome of ST-segment elevation myocardial infarction in patients without prior history of coronary artery disease.

INTRODUCTION: Early statin treatment has beneficial effects on the prognosis after acute coronary syndromes. We investigated the impact of prior statin treatment on the outcome of patients without a prior history of coronary artery disease (CAD) who presented with ST-elevation myocardial infarction (STEMI) and were treated with thrombolysis. METHODS: The study enrolled 1032 consecutive patients who satisfied the above criteria. They were categorized into two groups, based on their prior statin treatment for at least 3 months before admission: the statin pretreatment group (n=124) and the statin-naïve group (n=908). All patients received high-dose statins during hospitalization and were prescribed statins after discharge. The primary outcome was the incidence of successful thrombolysis, as expressed by the percentage of patients with 50% ST-segment resolution and complete retrosternal pain resolution at 90 minutes. Secondary outcomes included reduction in high-sensitivity C-reactive protein (hs-CRP) and CK-MB levels, and in-hospital, short- and long-term cardiovascular mortality. RESULTS: ST-segment resolution 50% was observed in 63.7% of the statin-pretreatment group and in 49.1% of statin-naïve patients (p<0.01). Statin pretreatment was associated with lower hs-CRP and peak CK-MB levels (p<0.001). The statin-pretreatment group had lower 30-day mortality (5.6% vs. 12.3%, p<0.05), whereas no significant differences were detected in in-hospital or 3-year mortality. CONCLUSIONS: Prior statin treatment in patients without a history of CAD who present with STEMI is associated with successful thrombolysis, decreased systemic inflammation, a lesser degree of myocardial damage, and a possible reduction in short-term mortality.

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.