Gergely Feher

Cardioprotection by resveratrol: A human clinical trial in patients with stable coronary artery disease

Several beneficial effects of resveratrol (RES), a natural antioxidant present in red wine have already been described. The aim of our study was to investigate if RES had a clinically measurable cardioprotective effect in patients after myocardial infarction. In this double-blind, placebo controlled trial 40 post-infarction Caucasian patients were randomized into two groups. One group received 10 mg RES capsule daily for 3 months. Systolic and diastolic left ventricular function, flow-mediated vasodilation (FMD), several laboratory and hemorheological parameters were measured before and after the treatment. Left ventricular ejection fraction showed an increasing tendency (ns) by RES treatment. However, left ventricular diastolic function was improved significantly (p < 0.01) by RES. A significant improvement in endothelial function measured by FMD was also observed (p < 0.05). Low-density lipoprotein (LDL) level significantly decreased (p < 0.05) in the RES treated group. Red blood cell deformability decreased and platelet aggregation increased significantly in the placebo group (p < 0.05), while resveratrol treatment has prevented these unfavourable changes. Concerning other measured parameters no significant changes were observed neither in placebo nor in RES group. Our results show that resveratrol improved left ventricle diastolic function, endothelial function, lowered LDL-cholesterol level and protected against unfavourable hemorheological changes measured in patients with coronary artery disease (CAD).

The genetics of antiplatelet drug resistance

Platelets have a central role in the development of arterial thrombosis and subsequent cardiovascular events. An appreciation of this complex process has made antiplatelet therapy the cornerstone of cardiovascular disease management. However, numerous patients will experience a recurrent atherothrombotic vascular event despite adequate antiplatelet therapy. Individual differences in the rate of platelet activation and reactivity markedly influence normal hemostasis and the pathological outcome of thrombosis. Such an individual variability is largely determined by environmental and genetic factors. These are known to either hamper platelets’ response to agonists, and thereby mimic the pharmacological modulation of platelet function or mask therapy effect and sensitize platelets. In this article, we reviewed the antiplatelet mechanisms of aspirin and clopidogrel and the possible role of different polymorphisms, which may affect the efficacy of antiplatelet therapy. Heterogeneity in the way patients respond to aspirin and clopidogrel may in part reflect variation in cyclooxygenase (COX)‐1, COX‐2, glycoprotein (GP) Ib alpha, GP Ia/IIa, GP IIb/IIIa, UGT1A6*2, P2Y1, P2Y12, CYP2C9, CYP3A4 and CYP3A5 genotypes.

Diabetic Neuropathies: Diagnosis and Management

Introduction: Changes in human behaviour and lifestyle over the last century have resulted in a dramatic increase in the incidence of diabetes worldwide. Neuropathy is a common and costly complication of both type 1 and type 2 diabetes. The prevalence of neuropathy is estimated to be about 8% in newly diagnosed patients and greater than 50% in patients with long-standing disease. There are two main types of diabetic neuropathies, named as sensorimotor and autonomic neuropathies. Sensorimotor neuropathy is marked by pain, paraesthesia and sensory loss, and autonomic neuropathy may contribute to myocardial infarction, malignant arrhythmia and sudden death. Methods: In this article we reviewed the pathogenesis, clinical manifestations diagnosis and treatment of diabetic neuropathies. Conclusion: Sensorimotor and autonomic neuropathies (cardiovascular, gastrointestinal and genitourinary autonomic neuropathies) are common in diabetic patients. Apart from strict glycaemic control, no further therapeutic approach exists in the prevention of this phenomenon. Intensive diabetes therapy, intensive multifactorial cardiovascular risk reduction and lifestyle intervention are recommended in patients with cardiovascular autonomic neuropathy. Gastroparesis is the most debilitating complication of gastrointestinal autonomic neuropathy and genitourinary autonomic neuropathy can cause sexual dysfunction and neurogenic bladder; these conditions are hard to manage. The symptomatic treatment of sensory symptoms includes tricyclic antidepressants, serotonin and norepinephrine reuptake inhibitors, gabapentin, pregabalin and opioids. Other treatment strategies are not so effective.

Glycoprotein IIIA Gene (PIA) Polymorphism and Aspirin Resistance: Is There Any Correlation?

BACKGROUND: Platelet glycoprotein (GP) IIb/IIIa receptors play an inevitable role in platelet aggregation. The GP IIIa gene is polymorphic (PIA1/PIA2) and the presence of a PIA2 allele might be associated with an increased risk for acute coronary syndrome (ACS). OBJECTIVE: To examine the prevalence of the PIA2 allele in patients with ACS and in subjects with or without aspirin resistance. METHODS: The prevalence of the PIA2 allele was assessed in 158 patients with ACS and PIA2 compared with its prevalence in 199 healthy volunteers. The antiplatelet efficacy of aspirin was examined in all patients with ACS, as well as in 69 individuals who had suffered ischemic stroke and in 58 high-risk subjects without any known ischemic vascular events. RESULTS: PIA2 prevalence was significantly higher in patients with ACS (59/158) than in the control group (51/199; p < 0.05). Carriers of the PIA2 allele had a significantly higher risk of developing ACS, even after an adjustment to the risk factors (OR 5.74; 95% CI 1.75 to 18.8; p = 0.004). The occurrence of the PIA2 allele was significantly higher among patients with aspirin resistance than in subjects who demonstrated an appropriate response to the drug (allele frequencies, 0.21 vs 0.14; p < 0.05). All patients homozygous for the PIA2 allele had an inadequate platelet response to aspirin. CONCLUSIONS: Our results support the hypothesis that carriers of the PIA2 allele might have an increased risk for ACS. PIA2 homozygosity was associated with an inadequate response to aspirin therapy. Our data further suggest that patients with PIA2 allele homozygosity might benefit from antiplatelet therapy based on adenosine diphosphate antagonists throughout secondary treatment for prevention of ACS.

Aspirin resistance: possible roles of cardiovascular risk factors, previous disease history, concomitant medications and haemorrheological variables.

Background and objectiveRecent studies have described the incidence (approximately one in eight high-risk patients will experience a further atherothrombotic event over a 2-year period) of aspirin (acetylsalicylic acid) resistance and its possible background. The aim of this study was to compare the characteristics (risk profile, previous diseases, medications and haemorrheological variables) of patients in whom aspirin provided effective platelet inhibition with those in whom aspirin was not effective in providing platelet inhibition.Methods599 patients with chronic cardio- and cerebrovascular diseases (355 men, mean age 64 ±11 years; 244 women, mean age 63 ± 10 years) taking aspirin 100–325 mg/day were included in the study. Blood was collected between 8:00am and 9:00am from these patients after an overnight fast. The cardiovascular risk profiles, history of previous diseases, medication history and haemorrheological parameters of patients who responded to aspirin and those who did not were compared. Platelet and red blood cell (RBC) aggregation were measured by aggregometry, haematocrit by a microhaematocrit centrifuge, and plasma fibrinogen by Clauss’ method. Plasma and whole blood viscosities were measured using a capillary viscosimeter.ResultsCompared with aspirin-resistant patients, patients who demonstrated effective aspirin inhibition had a significantly lower plasma fibrinogen level (3.3 g/L vs 3.8 g/L; p < 0.05) and significantly lower RBC aggregation values (24.3 vs 28.2; p < 0.01). In addition, significantly more patients with effective aspirin inhibition were hypertensive (80% vs 62%; p < 0.05). Patients who had effective platelet aggregation were significantly more likely to be taking β-adrenoceptor antagonists (75% vs 55%; p < 0.05) and ACE inhibitors (70% vs 50%; p < 0.05), whereas patients with ineffective platelet aggregation were significantly more likely to be taking HMG-CoA reducíase inhibitors (statins) [52% vs 38%; p < 0.05]. Use of statins remained an independent predictor of aspirin resistance even after adjustment for risk factors and medication use (odds ratio 5.92; 95% CI 1.83, 16.9; p < 0.001).ConclusionsThe mechanisms underlying aspirin resistance are multifactorial. Higher fibrinogen concentrations increase RBC aggregation and can also result in increased platelet aggregation. The higher rate of hypertension in patients with effective platelet aggregation on aspirin could explain the differences in β-adrenoceptor antagonist and ACE inhibitor use between these patients and aspirin-resistant patients. Furthermore, an additive effect of these drugs may contribute to effective antiplatelet therapy. It is also possible that drug interactions with statins might reduce aspirin bioavailability and/or activity, thereby reducing platelet inhibition in aspirin-resistant patients.

Aspirin Resistance : Focus on Clinical Endpoints

Introduction: Via its antiplatelet effect, aspirin reduces the odds of an arterial thrombotic event in high-risk patients by approximately 25%. However, 10% to 20% of patients with an arterial thrombotic event who are treated with aspirin have a recurrent arterial thrombotic event during long-term follow-up. Nevertheless, the effectiveness of aspirin has been questioned by the emergence of the concept of aspirin resistance, which has been introduced as an explanation of the fact that a considerable proportion of patients treated with aspirin exhibit normal platelet function. Objectives and Methods: We systematically reviewed all available evidence till March 2008 on prevalence of aspirin resistance and its association with clinical outcome. We also collected articles showing the possible way of treatment. Conclusion: Analyzing the data of different laboratory methods aspirin resistance seems to be associated with poor clinical outcome, although currently no standardized or widely accepted definition of aspirin resistance exists. The widely used laboratory methods might not be comparable with each other; therefore, specific treatment recommendations for patients who exhibit high platelet reactivity during aspirin therapy or who have poor platelet inhibition by aspirin are not established.

The role of vinpocetine in the treatment of cerebrovascular diseases based on human studies

INTRODUCTION It shows the importance of cerebrovascular diseases that they are the third main cause of death exceeded only by coronary artery diseases and cancer. Cerebral ischemia leads to irreversible brain damage, thereby it is important to rescue the hypoperfused areas. Patients without stroke but with chronic cerebral hypoperfusion can also benefit from the increasing of the cerebral blood flow. METHODS The aim of this review was to summarize the indications and the potential effects of vinpocetine in acute and chronic cerebrovascular diseases based on clinical studies. RESULTS There is no evidence that vinpocetine treatment is applicable in acute ischemic stroke, only few study with low patient number showed a slight but significant improvement in the patients conditions. In chronic cerebrovascular patients after single dose and long-term vinpocetine therapy, PET, TCD, SPECT and NIRS examinations showed increasing perfusion and elevated glucose and O 2 consumption of the examined areas, furthermore significant improvement of the rheologic factors was detected. A meta-analysis of international clinical studies showed a significant improvement in cognitive achievement in chronic stroke patients after oral therapy. CONCLUSION The cited studies showed the potential multi-pharmacological effects of vinpocetine and its beneficial hemorheological potential. The drug also improves the blood flow and the metabolism of the affected brain areas. There is increasing evidence that vinpocetine improves the quality of life in chronic cerebrovascular patients.

Inhibition of ADP-evoked platelet aggregation by selected poly(ADP-ribose) polymerase inhibitors.

Pathologic platelet activation has been implicated in the pathogenesis of ischemic heart disease. Since cardiomyocytes can be protected from ischemia-reoxygenation injury by poly(ADP-ribose) polymerase (PARP) inhibitors mimicking the adenine/ADP part of NAD+, their structural resemblance to ADP may also enable the blockade of platelet aggregation via binding to ADP receptors. Blood samples drawn from healthy volunteers were pre-incubated with different concentrations of PARP inhibitors: 4-hydroxyquinazoline, 2-mercapto-4(3 H)-quinazolinone, or HO-3089. ADP-, collagen- and epinephrine-induced platelet aggregation was evaluated according to the method described by Born. The effect of PARP inhibitors on thrombocyte aggregation was also examined when platelets were sensitized by heparin and in the presence of incremental concentrations of ADP. All examined PARP inhibitors reduced the ADP-induced platelet aggregation in a dose-dependent manner (significant inhibition at 20 &mgr;M for HO-3089 and at 500 &mgr;M for the other agents; P < 0.05), even if platelets were sensitized with heparin. However, their hindrance on platelet aggregation waned as the concentration of ADP rose (no effect at 40 &mgr;M ADP). PARP inhibitors had minimal effect on both collagen- and epinephrine-induced platelet aggregation. Our study first demonstrates the feasibility of a design for PARP inhibitors that does not only protect against ischemia-reperfusion-induced cardiac damage but may also prevent thrombotic events.

Thrombosis Preventive Potential of Chicory Coffee Consumption: A Clinical Study

The protective effects of plant polyphenol intake on cardiovascular morbidity and mortality are widely acknowledged. Caffeine‐free chicory coffee is a rich source of plant phenolics, including caffeic acid, which inhibits in vitro platelet aggregation, and also phenylpyruvate tautomerase enzymatic activity of the proinflammatory cytokine, macrophage migration inhibitory factor (MIF). To assess whether chicory coffee consumption might confer cardiovascular benefits a clinical intervention study was performed with 27 healthy volunteers, who consumed 300 mL chicory coffee every day for 1 week. The dietary intervention produced variable effects on platelet aggregation, depending on the inducer used for the aggregation test. Whole blood and plasma viscosity were both significantly decreased, along with serum MIF levels, after 1 week of chicory coffee consumption. Moreover, significant improvements were seen in red blood cell deformability. No changes in hematocrit, fibrinogen level or red blood cell counts were detected. The full spectrum of these effects is unlikely to be attributable to a single compound present in chicory coffee, nevertheless, the phenolics, including caffeic acid, are expected to play a substantial role. In conclusion, our study offers an encouraging starting‐point to delineate the antithrombotic and antiinflammatory effects of phenolic compounds found in chicory coffee. Copyright

Relation of platelet aggregation and fibrinogen levels to advancing age in aspirin- and thienopyridine-treated patients

In our present study we investigated the association between platelet aggregation in patients treated with the most widely used antiplatelet agents (100 and 300-325 mg acetylsalicylic acid (ASA), 75 mg clopidogrel, 500 mg ticlopidine and the combination of 100 mg aspirin and 75 mg clopidogrel), fibrinogen levels and aging. Between 2001 and 2005 we measured in vitro platelet aggregation in 5026 vascular patients according to the method of Born. Platelet aggregation was tested with 5 and 10 microM adenosine-diphosphate, 2 microg/ml collagen and 10 microM epinephrine stimulants. Fibrinogen level was simultaneously measured in a subgroup of 3243 patients. The subjects were divided by age into decades. Platelet aggregation increased significantly with advancing age in the case of 100 and 300-325 mg ASA-treated patients (p<0.001). In aspirin-treated patients also fibrinogen levels increased with aging (p<0.001). There was no association between platelet aggregation or fibrinogen levels and aging either in patients treated with 75 mg clopidogrel or with 500 mg ticlopidine. Thienopyridine-treated patients exhibited significantly lower fibrinogen levels than ASA-treated individuals (p<0.001). Our results suggest that advancing age is associated with elevated platelet aggregability in widely used antiplatelet regimens that might contribute to higher risk of cardiovascular events in the elderly.