Risk Factor For Ischemic Events Research Articles

Abstract 3472: The Prediction of Ischemic Events After Percutaneous Coronary Intervention by Platelet Reactivity to Adenosine Diphosphate: First Evidence for an Oral Antiplatelet Therapeutic Target Determined by an Ex Vivo Test of Platelet Function.

Background: High on-treatment platelet reactivity to adenosine diphosphate (HPR-ADP) may be a risk factor for ischemic events after percutaneous coronary intervention (PCI). We determined whether a cutpoint of HPR-ADP, similar to the INR used to guide anticoagulant therapy, could predict ischemic event occurrence after PCI. Methods : Post-procedural platelet reactivity to ADP was measured by conventional aggregometry in 352 consecutive patients undergoing non-emergent PCI followed for up to 2 years for post-discharge ischemic events. All patients had received clopidogrel and aspirin therapy at the time of aggregation measurements. Results: Eighty-two patients (23%) suffered ischemic events and had higher 5 and 20 μM ADP-induced aggregation compared to patients without ischemic events (46 ± 14% and 60 ± 13% versus 30 ± 17% and 43 ± 19%, respectively, p<0.0001 for both measurements). Using a combined receiver operator curve analysis, HPR-ADP cutpoints of 46% aggregation following 5μM ADP stimulation and 59% aggregation following 20μM ADP stimulation were associated with 63% and 74% of ischemic events, respectively. Multivariate Cox regression demonstrated significance between events and post-procedural HPR-ADP cutpoints (20μM ADP, OR=8.6, p<0.0001; and 5μM ADP, OR=2.9, p=0.01). Conclusions: High on-treatment platelet reactivity to ADP is an independent risk factor for ischemic events within 2 years of non-emergent PCI. These data are the first to support a therapeutic target for antiplatelet therapy based on an ex vivo platelet function test, similar to the INR used for anticoagulant therapy. The study is a step towards a personalized medicine approach to guide the intensity of antiplatelet therapy.

Lipoproteína(a) e inibição da fibrinólise na doença arterial coronariana

O envolvimento da lipoproteína(a) nas doenças ateroscleróticas tem sido alvo de muitos estudos que têm demonstrado que esta lipoproteína é um fator de risco independente para a doença arterial coronariana (DAC). Devido à semelhança estrutural com o plasminogênio, a Lp(a) pode competir com os sítios de ligação deste, diminuindo a geração de plasmina e inibindo a fibrinólise. O trombo formado numa placa aterosclerótica rompida dispara a maioria dos eventos cardiovasculares isquêmicos. Como o trombo é dissolvido através do sistema fibrinolítico, surgiu a hipótese de que uma diminuição da atividade fibrinolítica poderia ser um fator de risco para eventos isquêmicos. Entretanto, alguns estudos demonstraram ausência de associação entre Lp(a) e DAC, enquanto alguns atribuem o real valor preditivo à uma sub-população de Lp(a) com alta afinidade por fibrina. Essa hipótese sugere que alguns fenótipos de Lp(a) não estão associados à aterotrombose. Sendo assim, as pesquisas envolvendo Lp(a) e DAC apresentam resultados controversos, altamente dependentes da população estudada. Na população brasileira, a qual apresenta uma heterogeneidade de etnias, são raros os estudos deste tipo. Diante das notáveis controvérsias, espera-se que a presente revisão possa contribuir para suscitar ânimos no sentido da realização de estudos adicionais envolvendo a dosagem da Lp(a) em pacientes com DAC na nossa população. O conhecimento acumulado ao longo do tempo sobre a associação entre Lp(a) e DAC foi obtido através de estudos conduzidos fora do nosso meio. Assim, estudos fundamentados dentro da nossa realidade poderão trazer respostas mais fidedignas e adequadas para a nossa população.

Platelet Reactivity in Patients and Recurrent Events Post-Stenting: Results of the PREPARE POST-STENTING Study

We investigated the relation of high ex vivo platelet reactivity, rapid fibrin generation, and high thrombin-induced clot strength to postdischarge ischemic events in patients undergoing percutaneous coronary intervention (PCI). High platelet reactivity and rapid fibrin generation may affect the incidence of ischemic events after PCI. However, limited data is available to link these ex vivo markers to the occurrence of events. We measured platelet reactivity to adenosine diphosphate (ADP) by light transmittance aggregometry (LTA) in patients undergoing PCI (n = 192). Clot strength, a measure of thrombin-induced fibrin and platelet interactions, and the time to initial fibrin generation, a marker of thrombin activity, were measured by thrombelastography. The relation of these measurements to ischemic event occurrence was prospectively examined over six months. A total of 100% and 84% of patients were on aspirin and clopidogrel therapy, respectively, at the time of the initial event. Posttreatment ADP-induced aggregation by LTA (63 +/- 12% vs. 56 +/- 15%, p = 0.02) and clot strength (MA) were higher (74 +/- 5 mm vs. 65 +/- 4 mm, p < 0.001) and time to initial fibrin generation was shorter (4.3 +/- 1.3 min vs. 5.9 +/- 1.5 min, p < 0.001) in patients with events (n = 38). The event rates in the highest quartiles of LTA and MA were 32% and 58%, respectively. High platelet reactivity and clot strength, and rapid fibrin formation are novel risk factors for ischemic events after PCI. Clot strength is more predictive than ADP-induced platelet aggregation and may explain the occurrence of events despite treatment with cyclooxygenase-1 and P2Y12 inhibitors.

Culprit Factors for the Failure of Well-Conducted Warfarin Therapy to Prevent Ischemic Events in Patients With Atrial Fibrillation

In patients with atrial fibrillation (AF), oral anticoagulant therapy (OAT) is effective in reducing stroke and embolism. However, despite OAT, ischemic events do occur in some patients. Studies specifically addressing the identification of risk factors for ischemic events during well-conducted OAT are not available. In this study, we prospectively investigated the role of classic risk factors and homocysteine levels in the occurrence of ischemic complications in 364 AF patients on OAT. The quality of anticoagulation levels and the occurrence of bleeding and thrombotic events were recorded. During follow-up (859 patient years) 21 patients had ischemic complications (rate 2.4 x 100 patient-years). Homocysteine plasma levels were higher in these patients than in patients without ischemic complications during OAT (P<0.01), whereas no difference was observed in relation to the quality of OAT. The presence of a history of previous ischemic events, hypertension, and homocysteine plasma levels over the 90th percentile were all associated with an increased risk of ischemic events during OAT (odds ratio [OR]=7, 4.5, and 4.7, respectively). The coexistence of these risk factors markedly increased the risk (OR=13.1; 95% CI, 3.7 to 45.7; P=0.001). In conclusion, our results indicate that AF patients with multiple risk factors may not be sufficiently protected by OAT, even when this is well conducted.

Blood Oxygen Level–Dependent MRI of Cerebral CO 2 Reactivity in Severe Carotid Stenosis and Occlusion

Impaired cerebrovascular reserve capacity (CVC) is a risk factor for ischemic events in patients with high-grade carotid stenosis and occlusion. In this study, the CVC in response to a CO2 challenge was evaluated with blood oxygen level-dependent (BOLD) MRI and the results compared with those of a transcranial Doppler CO2 tests. A T2*-weighted single-shot multigradient echo-planar imaging sequence was used to determine cerebral CO2 reactivity. T2* values were calculated for each pixel at rest and during a challenge with 7% CO2, and a reference function was fitted to the T2* time courses. Whole-brain color-coded DeltaT2* parameter maps were calculated and visually evaluated for regional differences. Additionally, a region-of-interest analysis was undertaken. Average values for DeltaT2* normalized to changes in end-tidal PCO2 were calculated. Color parameter maps showed areas of decreased BOLD effect within the internal carotid artery territory in 12 of 13 hemispheres with impaired CVC in transcranial Doppler CO2 test. Regional normalized DeltaT2* was highly correlated with changes of middle cerebral artery blood flow velocity in transcranial Doppler CO2 test. Normalized DeltaT2* was significantly reduced in hemispheres with impaired CVC in transcranial Doppler (P<0.0001). BOLD MRI can easily be included in routine MRI exams. The technique is robust and yields diagnostic information concerning the cerebrovascular reserve.

Hyperhomocysteinemia and vitamin B 6 deficiency: New risk markers for nonvalvular atrial fibrillation?

Background A recent “ex-vivo” study showed that nonvalvular atrial fibrillation (NVAF) is associated with enhanced activity of metalloproteinases at the atrial level, and in animal models homocysteine (Hcy) is able to activate metalloproteinases. The aim of this case-control study was to investigate the association of total Hcy plasma levels, vitamin status (folate, vitamin B 6, and vitamin B 12), and methylenetetrahydrofolate reductase C677T and CBS 844ins68 polymorphisms with NVAF. Furthermore, the role of these variables in the occurrence of ischemic events was investigated. Methods We studied 310 NVAF patients on oral anticoagulant treatment (168 patients with previous ischemic events and 142 without) and 310 controls. Results Hyperhomocysteinemia (highest quartile) and vitamin B 6 deficiency (lowest quartile) were independently associated with NVAF after multivariate analysis (Hcy: odds ratio [OR] 6.40, 95% CI 3.29–12.46; vitamin B 6: OR 3.02, 95% CI 1.02–8.95). A significant correlation was found between Hcy levels and left atrial diameter ( r = 0.46; P < .001). As shown by multivariate analysis, elevated Hcy levels were an independent risk factor for ischemic complications during NVAF (OR 2.66, 95% CI 1.15–6.20). Conclusions This study demonstrates a significant association of both elevated Hcy levels and low vitamin B 6 levels with the presence of NVAF; in addition, it confirms the role of Hcy as a risk factor for ischemic events during NVAF.

Prospective Evaluation of Hypertensive Patients with Carotid Kinking and Coiling: An Ultrasonographic 7-Year Study

The aim of this study was to determine the incidence of vascular events during a 7-year follow-up evaluation in a group of 34 hypertensive patients with kinking of the internal carotid artery and 36 well-matched hypertensive control subjects. The carotid intima-media thickness (IMT) was measured at three points of the carotid bifurcation and at three points of carotid kinking on the ultrasonographic posterior wall. The mean IMT measured in the segment of the angular bending was lower than the mean values detected at the bifurcation in normal subjects and in hypertensives without carotid elongation (p < 0.01). At the carotid bifurcation of the same side of the kinking, there was an arterial IMT that was significantly lower as compared to the contralateral axis and to the measurements obtained in other hypertensive subjects. During a 7-year follow-up study, 10 vascular events occurred in the hypertensives with carotid kinking and 14 in the controls, without significant differences between the 2 groups. In hypertensives with carotid kinking, the mean IMT measured on the angular bending and at the ipsilateral carotid bifurcation was significantly lower than the values obtained at the contralateral bifurcation and in the other hypertensive subjects. In the 7-year follow-up study, moreover, the presence of carotid kinking does not impact the incidence of vascular events in the hypertensive population. Thus, the presence of carotid kinking in hypertensive subjects may not be considered a further risk factor for ischemic events.

The association between the diameter of a patent foramen ovale and the risk of embolic cerebrovascular events

PURPOSE: We sought to determine whether the size of a patent foramen ovale affected the risk of embolic cerebrovascular events of unknown origin. PATIENTS AND METHODS: We ascertained the presence and measured the size of patent foramen ovale using multiplane transesophageal echocardiography in 121 consecutive patients younger than 60 years who had transient ischemic attacks or ischemic strokes and in 123 control subjects. None of the patients had left heart, aortic, or carotid sources of embolism, or echocardiographic signs of elevated left or right atrial pressure. We used multivariate logistic regression to determine whether the size of the patent foramen ovale was an independent risk factor for cerebrovascular events. RESULTS: The mean (± SD) diameter of a patent foramen ovale was significantly larger in patients (4 ± 2 mm) than in control subjects (2 ± 1 mm, P <0.0001). A patent foramen ovale greater than 4 mm was associated with an increased risk of transient ischemic attacks [odds ratio (OR) = 3.4; 95% confidence interval (CI), 1.0 to 11, P = 0.04], ischemic strokes (OR = 12; 95% CI, 3.3 to 44, P = 0.0001), and, especially, having evidence of two or more strokes (OR = 27; 95% CI, 4.7 to 160, P = 0.0002). CONCLUSION: The diameter of a patent foramen ovale is an independent risk factor for ischemic events, especially recurrent strokes.

Angiotensin-Converting Enzyme Gene Deletion Polymorphism Determines an Increase in Frequency of Migraine Attacks in Patients Suffering from Migraine without Aura

Many authors have reported an association between the angiotensin-converting enzyme (ACE)-D allele and coronary heart disease and other cardiovascular diseases. The mechanism underlying the positive associations between the ACE-D alleles and diseases are not yet clear. Previous reports showed an association between migraine without aura and ACE-D allele polymorphism. The study is aimed to evaluate if the DD genotype could also be associated with the frequency and duration of migraine without aura. In 302 patients suffering from migraine without aura (at least for 1 year), with no history of cardiovascular diseases and major risk factors for ischemic events, the genotypes of the ACE gene, plasma ACE activity, and the frequency (weekly) and duration of migraine attacks were evaluated. No drugs were given before (4 weeks) and during the study. The same evaluations were performed in 201 subjects without migraine. The molecular biologist and the physician evaluating the patient data were blinded to the clinical history and ACE-DD gene determination. Genotypes were determined by polymerase chain reaction amplification. Plasma ACE activity was performed by the HPLC method. The groups were similar for sex, age and smoking habit (migraines: 302 patients (200 F/102 M), mean age 37.8 ± 8.2 years; control: 201 subjects (127 F/74 M), mean age 37.5 ± 9.3 years). Patients with migraine without aura showed higher incidence of the ACE-DD gene (48.34%) than control subjects (37.32%), p < 0.05. The frequency of migraine (average attacks per week) was higher in patients with DD (2.11 ± 1.9) than in patients with ID (1.54 ± 1.44), p < 0.05. No difference in duration of migraine attacks (hours per week) was observed. Plasma ACE activity was increased in patients with the ACE-DD gene. Our data suggest that ACE-DD gene polymorphism could have an important role in determining migraine attacks and the frequency of these attacks. Further data are needed through further studies, especially on the biomolecular level.

EFFECT OF COMBINED KIDNEY-PANCREAS TRANSPLANT ON THE LIPID PROFILE: ONE YEAR FOLLOW-UP

367 Patients with type 1 diabetes mellitus are known to be at high risk for cardiac and peripheral vascular events. Lipoprotein abnormalities are considered largely responsible for this elevated risk. We sought to assess the impact of kidney-pancreas (K-P) transplantation on the lipid abnormalities among a selected group of patients followed for at least one year. We obtained total cholesterol, HDL, LDL and triglyceride levels of 70 patients (56% male) prior to K-P transplant and again one year later. At one year, total apoA-I, apoA-II and apoB levels and serum Lp(a) levels were assessed. ApoE phenotype was also obtained in 55% of patients. Patients achieved good glycemic control; the mean hemoglobinA1c one year post-transplant was 5.4±0.9%. The mean creatinine at one year was 1.62±0.6 mg/dl. There was a statistically significant decrease in triglyceride levels and increase in HDL levels. There was no significant change in the total cholesterol and LDL levels, although there was a trend towards a decline in both.Table At one year, mean levels of apoA-I were 144.2± 24.9 mg/dl, apoA-II 47.3±10.7 mg/dl and apoB 100.5±22.3 mg/dl. The mean Lp(a) level was 14.8±16.4 mg/dl. Except for the mean Lp(a) level, which is somewhat lower, these are comparable to previously reported levels for diabetic transplant recipients. The predominant apoE phenotype was E3/3 (58.7%). E3/2 was found among 20%, E4/3 among 18.7% and E4/2 among 2.6% of patients. The results of our study demonstrate that diabetic patients show improved lipid profiles one year following K-P transplant, possibly related to the restoration of normal kidney function and glycemic control. This may partly explain the perceived improvement in vascular outcomes that has been noted among these patients; the increased use in recent years of anti-lipemic medications and anti-proliferative antihypertensive agents may also contribute. Our patients had a somewhat higher prevalence of the apoE 4 allele than has been previously noted. This is a risk factor for ischemic events among uremic patients; its contribution to an excess risk of vascular events among transplant patients has not been defined.

Deletion polymorphism in the angiotensin-converting enzyme gene in patients with a history of ischemic stroke.

We evaluated the genotypes of the angiotensin-converting enzyme (ACE) gene in 101 subjects with and 109 subjects without a history of ischemic stroke. All were attending a metabolic ward. The two groups were compared for major risk factors for ischemic events. Genotypes were determined by polymerase chain reaction with oligonucleotide primers flanking the polymorphic region in intron 16 of the ACE gene. Deletion polymorphism of the ACE gene (DD genotype) was shown to be more common in subjects with a history of stroke than in those without (relative risk, 1.76; confidence intervals, 1.02 to 3.05). A positive family history for ischemic complications of atherosclerosis was also more common in subjects with documented events (relative risk, 1.99; confidence intervals, 1.10 to 3.59). DD genotype and a positive family history were strong independent discriminators of cerebral ischemia. Plasma levels of tissue-type plasminogen activator (TPA) and plasminogen activator inhibitor-1 help identify subjects with a history of cerebral ischemic episodes. When such fibrinolytic variables were included in the analysis, the DD genotype still strongly and independently discriminated subjects with a stroke history and significantly interacted with TPA levels > 10 ng/mL in such identification. We conclude that in subjects attending a metabolic ward, homozygosity for a deletion polymorphism of the ACE gene consistently discriminates subjects with a stroke history. Interaction with TPA improves such identification.

Plasma Lipoprotein(a) Levels in Subjects Attending a Metabolic Ward

In this cross-sectional study we compared the abilities of lipoprotein(a) [Lp(a)], plasminogen activator inhibitor-1 (PAI-1), and tissue plasminogen activator (TPA) to discriminate between individuals with and without a history of stroke from among subjects in a metabolic ward. A total of 210 subjects (108 men and 102 women; mean age, 63.8 years; range, 31 to 86 years) provided plasma and DNA samples for the study. Of these, 51 men and 50 women had a history of ischemic stroke. The 109 subjects without a history of stroke were compared with those with such a history for major risk factors for ischemic events. Mean plasma TPA and PAI-1 levels significantly (P < .001) discriminated among subjects younger than 70 years with a history of stroke. The mean plasma Lp(a) level of stroke subjects (21.9 mg/dL) did not differ significantly from that of control subjects (15.2 mg/dL). However, among individuals < 70 years old, Lp(a) plasma levels > 50 mg/dL were more common among stroke patients (8 with versus 1 without, P < .01 by chi 2 test). A molecular variation in the 5' flanking region of the apo(a) gene that has been related to elevated Lp(a) plasma levels (G/A-914) was not strongly correlated with circulating levels of Lp(a), nor did Lp(a) levels correlate with a polymorphism of the apo(a) gene (G/A-21), which is strongly linked (P < .001) to the G/A-914 variation. In this setting, the relation between Lp(a) and cerebral ischemia appears to be limited to individuals below 70 years with elevated (> 50 mg/dL) plasma levels of the lipoprotein.

Abnormally high circulation levels of tissue plasminogen activator and plasminogen activator inhibitor-1 in patients with a history of ischemic stroke.

We evaluated 106 subjects with and 109 subjects without a history of ischemic stroke. All were attending a metabolic ward. The two groups were compared for major risk factors for ischemic events. A positive family history for ischemic complications of atherosclerosis was more common in subjects with a history of stroke than in those without; moreover, plasma levels of plasminogen activator inhibitor-1 (PAI-1) and tissue-type plasminogen activator (TPA) were higher in patients with documented previous events. A strong positive significant correlation was found between TPA and PAI-1 levels, and an interaction between age and TPA was observed when the sample was stratified according to ages being above or below 70 years. When the patient population was analyzed according to the number of ischemic events, it was found that 62 of the 106 subjects with a history of stroke had experienced more than one ischemic event. Under these conditions, the levels of TPA and PAI-1 still correlated with the occurrence of previous ischemic episodes. As in the whole patient sample, TPA was the strongest discriminator. We conclude that in subjects attending a metabolic ward, TPA and PAI-1 levels consistently help identify subjects with a history of cerebral ischemic episodes and that TPA is the strongest discriminator.