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.

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.

Genetic variability of matrix metalloproteinase genes in cardiovascular disease.

It is well established that matrix metalloproteinases (MMPs) contribute to the degradation of the extracellular matrix of coronary plaque and contribute to the thinning of the fibrous cap. As a result, the atheromatous plaque becomes unstable and prone to rupture with consequent clinical manifestations including acute coronary syndromes. Moreover, genetic polymorphisms of MMPs have been found to be associated with the concentration of circulating MMPs, and over the past decade, considerable efforts have been devoted to explore the relationships between MMPs polymorphisms and myocardial infarction risk among various populations. However, existing studies have yielded inconsistent results. Some observations have suggested that genetic variation that affects the expression of MMPs may contribute to the occurrence of myocardial infarction, whereas others reported no support for an association of MMPs polymorphisms with myocardial infarction susceptibility. Furthermore, the interpretation of these studies has been complicated by the use of different populations or different control sources. Therefore, further studies are required to evaluate the role of matrix metalloproteinases and especially the associated genetic polymorphisms in cardiovascular disease.

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.

Effects of rosuvastatin and allopurinol on circulating endothelial progenitor cells in patients with congestive heart failure: the impact of inflammatory process and oxidative stress.

OBJECTIVE: Endothelial progenitor cells (EPCs) contribute to the maintenance of endothelial integrity and function. We investigated the effects of rosuvastatin and allopurinol on the number of EPCs in patients with heart failure and aimed to provide insight into the molecular inflammatory and oxidative mechanisms that could be responsible for the alterations in EPC levels after treatment. METHODS: Sixty patients with systolic heart failure were randomized to receive rosuvastatin 10mg/d, allopurinol 300mg/d or placebo and followed up for 1 month. The number of CD34(+)/KDR(+) and CD34(+)/CD133(+)/KDR(+) EPCs in blood was evaluated by flow cytometry. Endothelial function was assessed by brachial artery flow-mediated dilation. Levels of markers of inflammation and oxidative stress were also determined. RESULTS: Circulating EPCs were significantly increased after rosuvastatin treatment (from 230 (170-380) and 10 (8-24) to 390 (230-520) and 19 (8-33) cells/10(6) lymphomonocytes, respectively, p=0.004 and p=0.008), whereas they remained unchanged in the other groups. The increase in EPC levels was not associated with the changes in the levels of the measured inflammatory and oxidative markers. CONCLUSION: Short-term treatment with rosuvastatin, but not allopurinol, significantly increases the number of circulating EPCs in patients with heart failure providing further insights into its role in these individuals. The impact of rosuvastatin on EPCs is not mediated by changes in inflammatory and oxidative status.

The activation of endothelin-1 pathway during methionine-induced homocysteinemia mediates endothelial dysfunction in hypertensive individuals.

OBJECTIVES: Endothelin-1 (ET-1) is a key regulator of arterial blood pressure in humans, and homocysteinemia is associated with increased oxidative stress. It is still unclear whether homocysteine-induced oxidative stress is implicated in the regulation of ET-1 expression. We examined the impact of acute homocysteinemia on endothelial function in hypertensive patients and healthy individuals, and the potential role of ET-1. METHODS: In this double-blind, placebo-controlled study, 39 hypertensive and 49 healthy individuals were randomized to receive high-dose vitamins (2 g vitamin C and 800IU vitamin E) or placebo followed by methionine loading 100 mg/kg body weight. Endothelium-dependent dilation (EDD) and endothelium-independent dilation (EID) of the brachial artery were evaluated by plethysmography, at baseline and 4 h postloading (4 h PML). ET-1 was measured by ELISA, whereas total lipid hydroperoxides (per-ox) levels were measured by a commercially available photometric technique. RESULTS: Acute, methionine-induced homocysteinemia decreased EDD in all study groups (P < 0.001 for all), whereas vitamins pretreatment failed to prevent this effect, despite the vitamins-induced reduction of peroxidation in the hypertensives group (P < 0.05). On the contrary, methionine loading significantly increased plasma ET-1 levels only in hypertensives (P < 0.05), an effect which was not prevented by antioxidant vitamins (P < 0.05). EID remained unchanged after methionine loading, in all study groups (P = NS for all groups). CONCLUSION: Experimental homocysteinemia rapidly blunts endothelial function in both hypertensive individuals and healthy individuals. The rapid elevation of ET-1 levels observed only in hypertensives, suggests that ET-1 may be the key mediator of homocysteine-induced endothelial dysfunction, independently of oxidative stress.

Effects of rosuvastatin on myeloperoxidase levels in patients with chronic heart failure: a randomized placebo-controlled study.

BACKGROUND: Studies indicate that myeloperoxidase (MPO) is associated with disease progression and severity in heart failure (HF), while it may provide a mechanistic link between inflammation and adverse cardiac remodeling. The mechanisms that regulate MPO are unclear, while it is unknown whether specific treatments such as HMG-CoA reductase inhibitors and xanthine oxidase inhibitors may modify MPO. Therefore in the present study we examined the effects of rosuvastatin and allopurinol on MPO levels in patients HF. METHODS: Sixty clinically stable patients with systolic HF were randomized to receive rosuvastatin 10mg/day, allopurinol 300mg/day or placebo and followed up for 1 month. Plasma levels of MPO and serum levels of soluble CD40 ligand, interleukin-6, and oxidized LDL were determined using ELISA. All measurements were made before and after 1-month treatment. RESULTS: Rosuvastatin significantly reduced plasma levels of MPO (p=0.003), which remained unchanged in the other groups. Furthermore, the change of MPO levels in the rosuvastatin-treated group was significantly different compared with the other groups (p<0.05). Rosuvastatin administration also led to a significant decrease in oxidized LDL (p=0.009), while the other inflammatory markers remained unchanged in all groups. In the total population, a significant correlation was observed between the baseline levels of MPO and hsCRP (r=0.275, p=0.027), fibrinogen (r=0.278, p=0.025), and sCD40L (r=0.288, p=0.021). CONCLUSIONS: Short-term treatment with rosuvastatin regulates inflammatory process in patients with heart failure by significantly reducing plasma levels of MPO. This finding reveals a novel pleiotropic effect of statins in patients with heart failure, and provides further insights into the pathophysiological mechanisms of MPO in heart failure.

Comparative effects of rosuvastatin and allopurinol on circulating levels of matrix metalloproteinases and tissue inhibitors of metalloproteinases in patients with chronic heart failure.

BACKGROUND: Patients with chronic heart failure (HF) are characterized by alterations in matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) levels. However, the impact of hypolipidemic and antioxidant treatment in MMPs and TIMPs is unknown. In the present study, we sought to compare the effects of statins and xanthine oxidase inhibitors on circulating levels of MMPs and TIMPs in patients with chronic HF. METHODS: Forty-two clinically stable patients with mild to moderate HF were randomized to receive rosuvastatin 10 mg or allopurinol 300 mg daily and followed up for 1 month. Serum levels of MMP-2, -9, TIMP-1, and -2 were measured before and after treatment. RESULTS: Levels of MMP-2 and -9 were significantly decreased in the rosuvastatin group (from 251±52 ng/ml and 400±206 ng/ml to 215±47 ng/ml and 309±166 ng/ml, p<0.001 and p<0.05 respectively), but not in the allopurinol group. In the rosuvastatin group, TIMP-2 levels were significantly increased (from 85±17 ng/ml to 93±16 ng/ml, p<0.05), while TIMP-1 remained unchanged. In the allopurinol group, no significant changes were observed regarding the levels of TIMPs. CONCLUSIONS: Short-term rosuvastatin but not allopurinol administration decreases MMP-2 and -9 and increases TIMP-2 levels.

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.

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.

Role of inflammation and oxidative stress in endothelial progenitor cell function and mobilization: therapeutic implications for cardiovascular diseases.

Endothelial progenitor cells (EPCs) are mobilized from the bone marrow into the peripheral circulation, home to sites of injury, and incorporate into foci of neovascularization, thereby improving blood flow and tissue recovery. Patients with cardiovascular diseases, including coronary artery disease, heart failure, hypertension, and diabetes, have been shown to exhibit reduced number and functional capacity of EPCs. Considerable evidence indicates that EPCs constitute an important endogenous system to maintain endothelial integrity and vascular homeostasis, while reduced number of EPCs has recently been shown to predict future cardiovascular events. Thus, enhancement of EPCs could be of potential benefit for individuals with cardiovascular diseases. The interplay between inflammation and oxidative stress is involved in the initiation, progression, and complications of cardiovascular diseases. Emerging evidence from in vitro and clinical studies suggests that inflammatory and oxidative changes influence EPC mobilization. Drugs with anti-inflammatory and antioxidant properties, currently administered to patients with cardiovascular diseases, such as statins, have been demonstrated to exert beneficial effects on EPC biology. A better understanding of the inflammatory and oxidative mechanisms leading to the numerical and functional impairment of EPCs would provide additional insight into the pathogenesis of cardiovascular disease and create novel therapeutic targets.

Acute effects of different alcoholic beverages on vascular endothelium, inflammatory markers and thrombosis fibrinolysis system.

BACKGROUND & AIM: Mild alcohol consumption has been associated with decreased cardiovascular risk, although the underlying mechanisms are still unclear. We compared the acute effects of several alcoholic beverages on endothelial function, inflammatory process and thrombosis/fibrinolysis system in young adults. METHODS: In this randomized intervention trial, healthy young individuals with no risk factor for atherosclerosis were randomized into 5 equally sized groups and received an equal amount of alcohol (30 g), as red wine (264 ml), white wine (264 ml), beer (633 ml), whisky (79 ml) or water (250 ml). Forearm blood flow was determined by gauge-strain plethysmography, at baseline, 1 and 4 h after alcohol intake. Levels of interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-alpha), C-reactive protein (CRP), fibrinogen (Fib), plasminogen activator inhibitor (PAI-1), von Willebrand factor (vWF) and tissue plasminogen activator (tPA) were determined at baseline and 4 h after alcohol consumption. RESULTS: Reactive hyperemia was significantly increased 1 h after beer and red wine consumption (p<0.05 for both), while it returned at baseline at 4 h (p=ns vs baseline) but remained unchanged in all the other groups. vWF was decreased in the beer and red wine groups (p<0.05 for both) only. PAI-1/tPA ratio remained unchanged only in red wine and control group. Inflammatory markers remained unchanged in all the groups. CONCLUSIONS: Acute consumption of red wine or beer improves endothelial function and decreases vWF levels, suggesting that the type of beverage may differently affect endothelial function and thrombosis/fibrinolysis system in healthy adults.