Burak Pamukcu

The role of aspirin resistance on outcome in patients with acute coronary syndrome and the effect of clopidogrel therapy in the prevention of major cardiovascular events.

AbstractBackground: Aspirin resistance may increase up to more then threefold the risk of major cardiovascular events (MACE) in patients with stable coronary artery disease. Aim:The aim of our study was to determine; the prevalence of aspirin resistance in patients with acute coronary syndromes, the role of aspirin resistance on outcome in the follow-up and the effect of clopidogrel therapy in the prevention of MACE in aspirin resistant subjects. Material and methods: We detected the prevelance of aspirin resistance in 105 patients with acute coronary syndrome. Platelet functions were analyzed in Platelet Function Analyzer (PFA)-100 (Dade Behring, Germany) with collagen and/or epinephrine (Col/Epi) and collagen and/or ADP (Col/ADP) cartridges. Primary end points of the study were myocardial infarction, unstable angina, cardiac death. Results: 19% (n = 20) of patients were aspirin resistant by PFA-100. In the follow-up, MACE occured in 9 patients (45%) with aspirin resistance and in 10 patients (11.7%) with aspirin sensitive platelet aggregation (p = 0.001). Multivariate analysis showed that aspirin resistance was an independant predictor of MACE. The prevalence of MACE in patients who were on clopidogrel treatment for 12 months were lower compared to those who were on a clopidogrel treatment for the first six months (p = 0.040). Conclusions: We determined that the MACE risk in patients with acute coronary syndromes having detected aspirin resistance, was higher at statistically significant levels compared to patients having aspirin sensitive platelet aggregation. Our results showed that aspirin resistance, was an independant predictor of MACE in patients with acute coronary syndrome.

Endothelial Function in Patients with Obstructive Sleep Apnea Syndrome but without Hypertension

Background: Obstructive sleep apnea syndrome (OSAS) influences endothelial function and causes hypertension. Objectives: Our aim was to evaluate the role of endothelial dysfunction in the pathogenesis of hypertension in OSAS. Methods: Twenty-three patients with OSAS but without hypertension and 15 healthy normotensive subjects were investigated. The presence or absence of OSAS was evaluated with a sleep study. Endothelial function was investigated with brachial artery ultrasound examination. Results: Baseline characteristics were equivalent between the two groups. Minimal oxygen saturation and apnea-hypopnea indexes in the OSAS and control groups were 62.9 ± 16.5 versus 94.9 ± 1.1% (p < 0.0001) and 53.1 ± 20.3 versus 3.8 ± 0.9 (p < 0.0001), respectively. There was not statistically significant difference between basal brachial artery diameters measured in the morning and in the evening in all groups. Flow-mediated dilation (FMD) values measured in the morning were lower than those measured in the evening in both OSAS patients and the control group: FMD of OSAS patients was 6.04 ± 3.18% in the morning and 10.38 ± 4.23% in the evening hours (p = 0.001), and FMD of control subjects was 10.9 ± 2.6% in the morning and 13.9 ± 2.32 in the evening hours (p = 0.002). Differences in FMD values measured both in the morning and evening hours in OSAS patients were lower compared with those in control subjects (p < 0.0001 in the morning hours and p = 0.003 in the evening hours). Conclusions: We detected a prominent diurnal deterioration in endothelial function in normotensive OSAS patients compared with healthy subjects. This deterioration may occur due to ongoing hypoxemia during the night and it may be a possible cause of hypertension and atherosclerotic cardiovascular diseases in patients with OSAS.

A review of aspirin resistance; definition, possible mechanisms, detection with platelet function tests, and its clinical outcomes

Aspirin (acetylsalicylic acid) is one of the main therapeutics in prevention of thrombo-embolic vascular events. Its efficiency is proved in the prevention of cardiovascular events. However, antiplatelet effect of aspirin is not absolute in all patients and some patients experience thrombo-embolic events despite aspirin. These patients are clinically called as aspirin resistant or aspirin non-responders. Globally, a lot of people are affected by aspirin resistance according to the high prevalence of athero-thrombotic vascular diseases. A prevalence of 5.5–45% in patients with various cardiovascular disease by different laboratory methods has been reported for aspirin resistance. Clinical outcome of aspirin resistance has been demonstrated in patients with different vascular diseases. Detection of platelet function in patients treated with aspirin may be necessary in the prediction of clinical outcome. Point of care methods, which have correlated results with the standard light transmittance aggregometry may be appropriate choices in the detection of platelets’ response to antiplatelet therapy. Adequate additional therapies may reduce atherothrombotic risks and major cardiovascular events rate in aspirin resistant subjects. None of the current researches advised the cessation of aspirin therapy. There is need to investigate the efficacy of additional adenosine diphosphate receptor antagonists or newer antiplatelet agents in aspirin resistant subjects. The intent of this paper is to review the literature discussing possible mechanisms, determination techniques, and clinical effects of aspirin resistance.

Clinical relevance of aspirin resistance in patients with stable coronary artery disease: a prospective follow-up study (PROSPECTAR).

Aspirin resistance may increase the risk of major adverse cardiac events (MACE) more than threefold in patients with stable coronary artery disease (CAD). This study aimed to determine the prevalence of aspirin resistance in patients with stable CAD, the role of aspirin resistance on outcome in the follow-up, and the effect of clopidogrel therapy in MACE prevention in aspirin-resistant individuals. We detected the prevalence of aspirin resistance in 234 patients with stable CAD. Platelet function was determined by PFA-100 with collagen and/or epinephrine and collagen and/or ADP cartridges. The mean follow-up time was 20.6 ± 6.9 months. The primary endpoints of the study were occurrence of myocardial infarction, unstable angina, stroke and cardiac death. Of patients, 22.2% (n = 52) were aspirin resistant by PFA-100. During follow-up, MACE occurred in eight patients (15.4%) with aspirin resistance and in 20 patients (11.0%) with aspirin-sensitive platelet aggregation (P = 0.269). MACE increased in aspirin-resistant patients after termination of clopidogrel therapy. Eleven patients experienced MACE after cessation of clopidogrel therapy (P < 0.001). The MACE risk in patients with stable CAD having detected aspirin resistance was similar compared with patients having aspirin-sensitive platelet aggregation by PFA-100. The MACE prevalence increased during follow-up, however, just after cessation of clopidogrel therapy.

Association of metabolic syndrome with impaired heart rate recovery and low exercise capacity in young male adults

Background  Impaired heart rate recovery (HRR) is a powerful predictor of overall mortality.

The role of exercise on platelet aggregation in patients with stable coronary artery disease: exercise induces aspirin resistant platelet activation.

Objectives: The aim of our study was to determine the relation between exercise stress test and aspirin resistance in patients with stable coronary artery disease.Background: Clinically aspirin resistance is defined as having thrombotic and embolic cardiovascular events despite regular aspirin therapy.Methods: We studied platelet functions of 62 patients with stable coronary artery disease and 20 subjects with normal coronary arteries by Platelet Function Analyzer (PFA-100, Dade Behring, Germany) at rest and after exertion with collagen and/or epinephrine (Col/Epi) and collagen and/or ADP cartridges. Closure time (CT) < 186 seconds was defined as aspirin resistance with Col/Epi cartridges of PFA-100. Symptom limited treadmill stress test (protocol of Bruce) was performed with Oxford Streslink TD-1 system.Results: 8 (12.9%) patients were aspirin resistant by PFA-100 (CT < 186s despite regular aspirin therapy) at rest. At the first minute of the recovery period of exercise stress test 14 (22.5%) patients were aspirin resistant by PFA-100. CTs with Col/ADP were respectively 89 ± 6 s (83–100s) and 89 ± 5 s (82–104s) at rest and after exercise (p = 0.107). 20.3% (11/54) of patients known as in vitro aspirin sensitives at rest had shorter CTs and 11.1% (6/54) had aspirin resistance after exercise (p = 0.004). There was no statistically significiant difference in platelet functions in the control group after exertion.Conclusion: We conclude that 11.1% of in vitro aspirin sensitive subjects at rest had aspirin resistance after exercise by PFA-100. In some individuals, exercise induced platelet activation is aspirin insensitive at usual antiplatelet doses. We need further clinical trials to optimize antiplatelet therapy in patients with coronary artery disease.

Association of genetic variants in Methylenetetrahydrofolate Reductase and Paraoxonase-1 genes with homocysteine, folate and vitamin B12 in coronary artery disease

Background The aim of the present study was to investigate the association between genetic variants in metylenetetrahydrofolate reductase (MTHFR) and Paraoxonase-1 (PON1) 55/192 genes and total homocysteine (tHcy), folate, B12 vitamin, and PON1 levels in patients with coronary artery disease (CAD). Methods The study included 235 patients with CAD and 268 healthy control subjects. Results LL and LM genotypes and L allele of PON1 55 were over-represented in patients. In contrast, MM genotype and M allele were more frequent in controls. QQ genotype and Q allele of PON1 192 and CT genotype of MTHFR were significantly diminished and QR genotype and R allele were significantly elevated in CAD patients compared with controls. The plasma tHcy were elevated but B12 levels were diminished in patients. PON1 55 and 192 genetic variants were significantly associated with PON1 activity, triglyceride, total cholesterol, tHcy and, high-density lipoprotein-cholesterol and low-density lipoprotein-cholesterol in patients, respectively. Conclusion Genetic variants of PON1 55/192 and MTHFR were associated with CAD.

Influences of genetic variants in interleukin-15 gene and serum interleukin-15 levels on coronary heart disease

Interleukin-15 (IL-15) is a potent proinflammatory cytokine that is now considered a key component of atherosclerosis. Proinflammatory gene polymorphisms lead to variations in the production and level of the proteins. In light of these findings, we hypothesized that variations in the gene coding for IL-15 influence the risk of coronary heart disease (CHD) by modulating the IL-15 levels. To test this hypothesis, we examined 5 single nucleotide polymorphisms (SNPs) in IL-15 gene and IL-15 levels in 102 patients with acute coronary syndrome (ACS), 102 patients with chronic ischemic stable CHD and 162 healthy control subjects. This study is the first report showing the influences of IL-15 gene variants and IL-15 levels on CHD. The five single nucleotide polymorphisms (SNPs) within the IL-15 gene, G367A, C267T, A14035T, C13687A, and A10504G were carried out by polymerase chain reaction/restriction fragment length polymorphism (PCR/RFLP). Serum IL-15 levels were significantly higher in both acute and chronic patients than in controls. Genetic variants of IL-15 gene and IL-15 levels were associated with CHD. In conclusion, our study supports the hypothesis that genetic variation in IL-15 gene and IL-15 levels influence the risk of CHD. Further studies are needed to confirm our hypothesis.

Investigation of early atherosclerotic changes in acromegalic patients

Background:  Functional and morphological changes of endothelium were risk factors for mortality attributed to atherosclerosis. Studies investigating early atherosclerotic alterations and the effect of the treatment of acromegaly on these alterations gave conflicting results.

Aspirin-resistant platelet aggregation in a cohort of patients with coronary heart disease.

Aspirin resistance could be defined as thrombotic and embolic cardiovascular events despite regular aspirin therapy. The study aimed to determine the profile and prevalence of aspirin resistance in coronary artery disease patients. We evaluated the prevalence of aspirin resistance in a cohort of 505 patients with the diagnosis of coronary artery disease taking 80–300 mg regular aspirin daily. Platelet functions were analyzed by the Platelet Function Analyzer (PFA)-100 with collagen and epinephrine cartridges and collagen and ADP cartridges. A closure time of 186 s or less with the collagen and epinephrine cartridge was defined as aspirin resistance. Of the patients, 118 (23.4%) were aspirin resistant by the PFA-100. Aspirin-resistant patients were more likely to be older than aspirin-sensitive patients (P = 0.024). No statistically significant differences between the aspirin-resistant and aspirin-sensitive individuals were present in gender, major risk factors of coronary artery disease, number and localization of involved coronary vessels, serum lipid levels, and blood counts. According to the high prevalence of coronary heart disease, many people are affected by aspirin resistance, which may play a role in adverse cardiovascular events. Monitoring of platelet function in patients with coronary heart disease may support the optimization of antiplatelet therapy with additional and/or alternative agents.