The Pl(A1/A2) polymorphism of glycoprotein IIIa and cerebrovascular events in hypertension: increased risk of ischemic stroke in high-risk patients

OBJECTIVE: The platelet GPIIIa plays a pivotal role in platelet aggregation. Previous studies showed an association between the GPIIIa Pl(A1/A2) polymorphism and coronary thrombosis, while there is only contrasting evidence about its role in stroke. We explored the possibility that this polymorphism represents a risk factor for stroke in hypertensive patients. METHODS: We studied two populations. In loco, we genotyped 140 hypertensive control individuals and 28 hypertensive patients with ischemic stroke. Furthermore, we performed an analysis of previously published data of 451 Sardinian hypertensive patients, already characterized and genotyped. RESULTS: Association analysis revealed that the Pl(A2) distribution was similar between hypertensive patients with and without stroke, but when considering a more homogeneous population of high-risk hypertensive patients, defined according to ESH/ESC 2003 guidelines, we observed that the frequency of the Pl(A2) allele was higher among stroke versus nonstroke patients (stroke, 46.4%; nonstroke, 22.6%; P = 0.01). The multiple regression analysis taking into account this polymorphism among other factors known to contribute to ischemic stroke confirmed the Pl(A2) allele as an additive risk factor for stroke (B = 0.986, Wald = 4.943, P < 0.03), increasing the risk of stroke by 2.9 (95% confidence interval = 1.23-6.85, P < 0.02). Similar results were obtained in the Sardinian population: in hypertensive patients with three or more risk factors, Pl(A2) increases the risk (odds ratio = 2.8, 95% confidence interval = 1.3-6.0, P < 0.001) and is an additive risk factor for stroke (B = 1.073, Wald = 6.920, P < 0.01). CONCLUSIONS: Our data suggest that the Pl(A2) polymorphism is a genetic determinant of ischemic stroke in a selected high-risk hypertensive population.     

Defective platelet response to arachidonic acid and thromboxane A(2) in subjects with Pl(A2) polymorphism of beta(3) subunit (glycoprotein IIIa)

The membrane complex alpha(IIb)beta(3) is the major receptor for fibrinogen and is involved in platelet adhesion and aggregation. Evidence has been presented that the Pl(A2) allele of the beta(3) Pl(A1/A2) gene polymorphism might be an independent risk factor for coronary thrombosis, but the matter is still controversial. We investigated the relationship between this polymorphism and possible alterations of platelet functions in vitro. The platelet adhesion to fibrinogen-coated microplate wells and the aggregation induced by several different agonists were tested in 63 healthy volunteers, among them, 49 subjects with Pl(A1/A1) polymorphism, 12 subjects with Pl(A1/A2) polymorphism and two subjects with (PlA2/A2) polymorphism. Subjects with PlA1/A2 polymorphism or with Pl(A2/A2) polymorphism showed significantly lower platelet responses as compared with Pl(A1/A1) subjects when either arachidonic acid or the thromboxane A(2) analogue, U46619, were used as agonists. In resting condition and after thrombin or ADP stimulation, platelet function was normal in all the subjects. An increased sensitivity to the anti-aggregatory effect of acetylsalicylic acid was observed in platelets from subjects with the Pl(A2) allele. Finally, using a flow-cytometric evaluation and determining the beta-thromboglobulin plasma levels, we did not find any evidence of a Pl(A2) platelet hyper-reactivity ex vivo. Our findings are not consistent with the hypothesis that the purported increase of cardiovascular risk in these subjects may be as a result of platelet hyperactivation. On the contrary, the Pl(A2) allele is associated with a platelet functional deficiency, specifically linked to the activation of the fibrinogen receptor by thromboxane A(2).     

Glycoprotein IIIa Pl(A) polymorphism associates with progression of coronary artery disease and with myocardial infarction in an autopsy series of middle-aged men who died suddenly.

Glycoprotein IIIa (GPIIIa) has a key role in the aggregation of thrombocytes, and it also mediates intimal hyperplasia after endothelial injuries; the possible association of the Pl(A1/A2) polymorphism of the gene for GPIIIa with coronary thrombosis and with the progression of coronary artery disease (CAD) is still to be confirmed. Therefore, the association of the Pl(A) polymorphism with the development of coronary atherosclerosis, coronary narrowing, and myocardial infarction (MI) was studied in a prospective, consecutive autopsy series of 300 middle-aged, white Finnish men (33 to 69 years) suffering sudden out-of-hospital or violent death. Coronary atherosclerosis was measured morphometrically and the coronary stenosis percentage determined from a cast rubber model of the coronary tree. We found a significant inverse relation (P=0.01) between the Pl(A2)-positive genotype and coronary artery stenosis. The frequency of possessing the Pl(A2) allele was significantly (odds ratio [OR] 0.45, 95% confidence interval [CI] 0.22 to 0.98) lower among men with >50% coronary stenosis (18.3%) than among those with <25% stenosis (32.9%). Although the Pl(A) polymorphism was not directly associated with MI, the Pl(A2) allele was present in 11 of the 22 men (50%) with MI and coronary thrombosis (OR 6.6, 95% CI 2.1 to 22.8) but in only 6 of the 47 (12.8%) with MI associated with severe stenosis in the absence of thrombosis. In line with this result, men possessing the Pl(A2) allele also had a larger area of fissured and ulcerated complicated lesions in their coronary arteries (P<0.05). The present results suggest that the Pl(A) polymorphism is involved in the development of CAD and MI. Men with the Pl(A2) allele may harbor more thin-walled, vulnerable coronary plaques, plaques prone to rupture, leading to massive, fatal thrombosis. In contrast, men homozygous for the Pl(A1) allele may more often show stable plaques and present with infarction caused by progressive coronary stenosis.     

Platelet glycoprotein IIb/IIIa Pl(A2)/Pl(A2) homozygosity associated with risk of ischemic cardiovascular disease and myocardial infarction in young men: the Copenhagen City Heart Study

OBJECTIVES: We tested the hypothesis that platelet glycoprotein (GP) IIb/IIIa Pl(A2)/Pl(A2) homozygotes or Pl(A1)/Pl(A2) heterozygotes versus Pl(A1)/Pl(A1) noncarriers have increased risk of ischemic cardiovascular disease and myocardial infarction (MI), stratified for age and gender. BACKGROUND: The GP IIb/IIIa Pl(A1)/Pl(A2) polymorphism influences aggregation of platelets; however, an association between ischemic cardiovascular disease and heterozygosity remains controversial, and association with homozygosity is largely unexplored. METHODS: We genotyped the participants of the Copenhagen City Heart Study, a prospective cardiovascular investigation of the Danish general population (n = 9,149, 22-year follow-up) and assessed the risk of ischemic cardiovascular disease in heterozygotes or homozygotes versus noncarriers. RESULTS: Of the participants, 70.0%, 27.3%, and 2.7% were noncarriers, heterozygotes, or homozygotes, respectively. Incidence of ischemic cardiovascular disease was 167 and 103 per 10,000 person-years in homozygous and noncarrier men (log-rank: p = 0.006), whereas this difference was not observed in women (p = 0.33) (genotype.gender interaction: p = 0.03). In homozygous versus noncarrier men <40 years of age, 40 to 50 years, and >50 years at entry, age-adjusted relative risks (RRs) of ischemic cardiovascular disease were 3.6 (1.4 to 9.0), 2.4 (1.3 to 4.6), and 1.0 (0.6 to 1.8), respectively (age.genotype interaction in men: p = 0.04); equivalent multifactorially adjusted RRs were 3.0 (1.1 to 8.0), 2.0 (1.0 to 3.9), and 1.0 (0.6 to 1.8), respectively. The corresponding age-adjusted RR values of MI in men were 5.2 (1.5 to 18), 3.5 (1.6 to 7.5), and 0.5 (0.1 to 1.5), respectively (age.genotype interaction in men: p = 0.002); equivalent multifactorially adjusted RRs were 3.8 (1.0 to 15), 3.1 (1.4 to 6.9), and 0.5 (0.2 to 1.5), respectively. CONCLUSIONS: Pl(A2)/Pl(A2) homozygosity is associated with a three-fold and four-fold risk of ischemic cardiovascular disease and MI in young men.     

Alcohol and sudden cardiac death

Objective—To assess the relation between alcohol intake and sudden cardiac death—ie, death within one hour of the onset of symptoms.     

Hypokalemia and sudden cardiac death

Worldwide, approximately three million people suffer sudden cardiac death annually. These deaths often emerge from a complex interplay of substrates and triggers. Disturbed potassium homeostasis among heart cells is an example of such a trigger. Thus, hypokalemia and, also, more transient reductions in plasma potassium concentration are of importance. Hypokalemia is present in 7% to 17% of patients with cardiovascular disease. Furthermore, up to 20% of hospitalized patients and up to 40% of patients on diuretics suffer from hypokalemia. Importantly, inadequate management of hypokalemia was found in 24% of hospitalized patients. Hypokalemia is associated with increased risk of arrhythmia in patients with cardiovascular disease, as well as increased all-cause mortality, cardiovascular mortality and heart failure mortality by up to 10-fold. Long-term potassium homeostasis depends on renal potassium excretion. However, skeletal muscles play an important role in short-term potassium homeostasis, primarily because skeletal muscles contain the largest single pool of potassium in the body. Moreover, due to the large number of Na⁺/K⁺ pumps and K⁺ channels, the skeletal muscles possess a huge capacity for potassium exchange. In cardiovascular patients, hypokalemia is often caused by nonpotassium-sparing diuretics, insufficient potassium intake and a shift of potassium into stores by increased potassium uptake stimulated by catecholamines, beta-adrenoceptor agonists and insulin. Interestingly, drugs with a proven significant positive effect on mortality and morbidity rates in heart failure patients all increase plasma potassium concentration. Thus, it may prove beneficial to pay more attention to hypokalemia and to maintain plasma potassium levels in the upper normal range. The more at risk of fatal arrhythmia and sudden cardiac death a patient is, the more attention should be given to the potassium homeostasis.     

心脏骤停和心脏性猝死

心脏性猝死(SCD)是目前社会关注的热点问题.2005年WHO的数据表明,在全球死于心脑血管疾病的约1700万人群中,40%～50%是SCD.SCD虽然有多种定义,但目前一般认为是在1 h内出现的由于心血管原因导致的非预期死亡事件或无目击者的死亡事件.心脏骤停(SCA)不等同于SCD,SCA如果救治失败会引起真正的SCD.     

The association between type 2 diabetes mellitus and A1/A2 polymorphism of glycoprotein IIIa gene

Abstract Glycoprotein IIIa (GpIIIa) is a membrane receptor, found in various tissues, that has two alleles: A1 and A2. Signalling cascade of GpIIIa is modulated by enzymes called calpains, proteases that may also influence glucose metabolism. There is one small study that shows a high association of A1/A2 polymorphism with type 2 diabetes mellitus. In our research we planned to evaluate the association of A1/A2 polymorphism with type 2 diabetes in a population of patients with ST elevation acute myocardial infarction (STEMI). The study comprised 352 individuals. From the cohort of patients hospitalised for STEMI we chose 113 patients with diagnosed diabetes (diabetic group) and 118 patients with STEMI and normal glucose metabolism (non-diabetic group). The population group consisted of 121 persons. Genotyping was performed by the restriction fragments length polymorphism (RFLP) method. The frequency of alleles in all groups was in Hardy-Weinberg equilibrium. The percentage of A2 allele carriers was comparable among all groups : 20.4% (diabetic patients), 23.7% (nondiabetic) and 21.5% (control group) (p>0.05). There was no significant difference in frequency of A2 allele among the groups. We have not observed any association between GpIIIa polymorphism with either type 2 diabetes or STEMI.     

Trans-fatty acids and sudden cardiac death

Sudden cardiac death (SCD) is usually due to ventricular fibrillation and can occur as a first manifestation of heart disease. Prevention of ventricular fibrillation and SCD with n-3 polyunsaturated fatty acids is well documented. Trans-fatty acids (TFA) in the diet and cell membranes might affect the risk of SCD as well. We review evidence from an observational study that high levels of trans-18:2 (9 cis-, 12 trans- and 9 trans-, 12 cis-isomers of linoleic acid) in red blood cell membranes are associated with markedly higher risk of SCD. In contrast, cell membrane levels of trans-18:1 (trans-isomers of oleic acid), the major TFA in foods, do not appear associated with higher risk of SCD. While further studies are needed to investigate possible effects of trans-18:2 on arrhythmia, it would be prudent to limit dietary intake of trans-18:2.     

Ventricular arrhythmias and sudden cardiac death

The evaluation of a patient at risk for ventricular arrhythmias and CAD begins with a thorough medical history and the standard ECG, followed by an assessment of LVEF and the presence of ischemia. The SAECG, HRV, microvolt TWA, and invasive EPS should be used in particular subgroups of patients to assist the clinician in risk stratification for VT, VF, and SCD. Amiodarone is the superior antiarrhythmic agent in reducing the recurrence of VT/VF and subsequent ICD shocks. In addition, amiodarone has been shown to reduce arrhythmic death, but has fallen short in reducing total mortality. At present, patients who have a severely reduced LVEF (≤30%) and a history of MI are at extremely high risk for SCD and require an ICD. Aggressive risk stratification of patients is crucial in reducing the incidence of SCD. Understanding the role of pharmacotherapy and device therapy alike in the treatment of these patients will decrease future arrhythmic events and death.

Conclusions

Sudden cardiac death is the major cause of death in this country. Great strides have been made in recognizing which patients are candidates for ICD insertion. What remains is a greater public awareness, increased access to external defibrillators in the community, and a better understanding both among medical practitioners and patients alike as to who would benefit from aggressive SCD risk stratification.     

Nerve sprouting and sudden cardiac death

The factors that contribute to the occurrence of sudden cardiac death (SCD) in patients with chronic myocardial infarction (MI) are not entirely clear. The present study tests the hypothesis that augmented sympathetic nerve regeneration (nerve sprouting) increases the probability of ventricular tachycardia (VT), ventricular fibrillation (VF), and SCD in chronic MI. In dogs with MI and complete atrioventricular (AV) block, we induced cardiac sympathetic nerve sprouting by infusing nerve growth factor (NGF) to the left stellate ganglion (experimental group, n=9). Another 6 dogs with MI and complete AV block but without NGF infusion served as controls (n=6). Immunocytochemical staining revealed a greater magnitude of sympathetic nerve sprouting in the experimental group than in the control group. After MI, all dogs showed spontaneous VT that persisted for 5.8+/-2.0 days (phase 1 VT). Spontaneous VT reappeared 13.1+/-6.0 days after surgery (phase 2 VT). The frequency of phase 2 VT was 10-fold higher in the experimental group (2.0+/-2.0/d) than in the control group (0.2+/-0.2/d, P<0.05). Four dogs in the experimental group but none in the control group died suddenly of spontaneous VF. We conclude that MI results in sympathetic nerve sprouting. NGF infusion to the left stellate ganglion in dogs with chronic MI and AV block augments sympathetic nerve sprouting and creates a high-yield model of spontaneous VT, VF, and SCD. The magnitude of sympathetic nerve sprouting may be an important determinant of SCD in chronic MI.     

J波与心脏性猝死

J波主要是因心室外膜复极1相Ito电流相对增大,使心室肌内外膜之间产生电位差引起J点上移而形成的圆顶形心电波。高危J波与恶性心律失常密切相关,是心脏性猝死的高危预警信号。