High Myocardial Infarction Research Articles

Abstract 308: Chronic Aspirin Treatment Possibly Poses a Risk to Ischemic Heart via Impairment of Cardiac Proteasome Functions

Background: Impaired cardiac proteasome (CP) has been reported in ischemia and heart failure. Recent data highlighted aspirin as an inhibitor of the ubiquitin-proteasome system, however, it’s unclear whether it affects CP functions. Objective: We investigated the influence of aspirin on CP in the rat model of myocardial infarction (MI). Methods and Results: MI, sham or normal male SD rats were injected intraperitoneally with high (300mg/kg), low (5mg/kg) aspirin or saline (control) once a day for seven weeks. Parallel experiments were performed in the hypoxia/reoxygenated cell model of primary human ventricular myocytes incubated with different concentrations of aspirin. Myocardial hypertrophy, cardiac function, cell viability and the functions of 26S, 20S and 19S, including the β1, β2 and β5 subunits of 20S were determined. The activity of 26S, 20S and 19S declined by about 30%, and β5, β2 and β1 by 40%, 20% and 30%, respectively, in the MI rats compared with the non-MI rats ( P <0.05). Compared with the saline-treated MI rats, 26S and 20S in high or low dose aspirin-treated MI rats further decreased by 30% and 20%, and β5 further decreased by 30% and 12%, and β1 by 40% and 30%, respectively, and their lost activity was correlated with compromised cardiac function in the MI rats. The dose-related and selective inhibition of β5 and β1 by aspirin was comparable to their protein expressions in the MI rats and in the cultured cells. However, the CP in the normal settings, or 19S and β2 in all the groups of animals or cultured cells were less affected by aspirin treatment. The impaired CP, dose-dependently enhanced by aspirin, led to the elevation of oxidative and ubiquitinated proteins in the MI rat hearts or in the hypoxia/reoxygenated cells. These aberrant proteins in turn constituted the ultimate causal factor for the cardiac dysfunction and the loss of cell viability. In vitro experiments confirmed that the purified CP from the MI rats or hypoxic cells, but was more susceptible to aspirin treatment, whereas the complexes in the normal settings appeared less affected by aspirin. Conclusions: Chronic aspirin treatment, via the dose-dependent and selective inhibition of CP, enhanced the ischemic CP dysfunction, which constitutes a potential risk factor for the ischemic heart.

Progestogen-Only Contraceptives and the Risk of Acute Myocardial Infarction: A Meta-Analysis

The association between combined oral contraceptives (OC) and the risk of myocardial infarction (MI) has been intensively studied, and conclusions are controversial. While progestogen-only contraceptives (POC) are commonly used worldwide, their impact on cardiovascular diseases is poorly investigated and remains unclear. We carried out a meta-analysis based on EMBASE- and MEDLINE-referenced literature corresponding to OC marketed since 1960. Eligible articles published in English language describing OC or POC use and MI outcome were reviewed, and relevant ones were extracted. All types of POC and route of administration were considered. Six case-control studies were identified. The combined odds ratio showed no increase in the MI risk with POC use (odds ratio = 1.07; 95% confidence interval, 0.62-1.84). This result was similar according to the route of administration, including implant, injectable, and oral POC. Data from observational studies suggest no increase in risk of MI with POC use. However, these results are based on limited data. Further investigations are needed, especially among women at high MI risk.

High platelet reactivity is associated with myocardial infarction in premenopausal women: a population-based case-control study.

Platelets are involved in the occlusion of coronary arteries after rupture of an atherosclerotic plaque. Furthermore, activated platelets release large quantities of growth factors, chemokines and interleukins that regulate inflammatory reactions. Therefore, we hypothesized that high basal platelet reactivity may contribute to an increased risk of myocardial infarction (MI) in premenopausal women. We assessed the relation between high platelet reactivity and MI in a population-based case-control study among premenopausal women (aged < 50 years). We used multivariable logistic regression to quantify the effect of high platelet reactivity, adjusted for potential confounders. Platelet reactivity was estimated by plasma levels of neutrophil activating peptide 2 (NAP-2), CXC chemokine ligand (CXCL)4, soluble glycoprotein 1b (sGPIb) and soluble P-selectin. High platelet reactivity (i.e. levels >or= 90th percentile control subjects) was associated with a 2- to 3-fold increased incidence of MI: the adjusted odds ratios (ORs) were 3.0 [95% confidence interval (CI) 1.4-6.4] for NAP-2, 2.2 (0.9-5.1) for CXCL4, 1.9 (0.7-4.6) for sP-selectin and 2.5 (1.1-5.7) for sGPIb. The incidence of MI dose-dependently increased when more markers were elevated. High platelet reactivity according to both NAP-2 and sGPIb was associated with an up to tenfold increased incidence (9.9, 95% confidence interval 2.0-48.3). High basal platelet reactivity was associated with a 2- to 3-fold higher incidence of MI compared with normal platelet reactivity in premenopausal women. Our results suggest that high basal platelet reactivity may contribute to a higher risk of MI.

Stronger symptoms of depression predict high coronary heart disease mortality in older men and women

Most cohort studies have found depressive symptoms to be associated with increased cardiovascular mortality in the elderly, but follow-up times have often been short and study populations small. To describe associations between stronger symptoms of depression and the risk of death from coronary heart disease (CHD) or myocardial infarction (MI) in elderly Finnish subjects free of CHD at the baseline. This study is a prospective population-based epidemiological and clinical twelve-year follow-up study in Lieto Health Centre, Finland. The basic population consisted of 1196 elderly (64 years of age or older) persons who lived in the municipality of Lieto in southwestern Finland in 1990. The occurrence of CHD was determined on the basis of electrocardiographic (ECG) findings, Rose questionnaire and the diagnoses in medical records. The persons with CHD were excluded from the study population. Symptoms of depression at the baseline were measured with the Zung Self-rating Depression Scale (ZSDS). Mortality was followed up for about 12 years. The Kaplan-Meier survival curves showed stronger symptoms of depression to be related to high risks of mortality from CHD or MI among men and women. According to the Cox model for men significant predictors for higher risk of CHD or MI mortality were stronger symptoms of depression, higher age and a large number of medications in use. When women were examined, significant predictors were stronger symptoms of depression and a large number of medications in use. Stronger symptoms of depression are an independent risk factor for high CHD or MI mortality in aged Finnish men and women free of CHD at baseline.

Relation between the A1166C angiotensin II type 1 receptor gene polymorphism and cardiovascular outcomes after myocardial infarction.

The A1166C polymorphism of the angiotensin II type 1 receptor (AT1R) gene, which appears to be the main receptor mediating the pleitropic vascular effects of angiotensin II in human beings, has been associated with the risk of myocardial infarction (MI), the severity of coronary vasoconstriction and the occurrence of sudden death. The question therefore arises whether the A1166C polymorphism constitutes a hereditary risk factor of survival after an acute myocardial infarction. In a large prospective study of 970 consecutive patients with a recent myocardial infarction the A1166C polymorphism was detected using a PCR based protocol. During the follow-up period (median, 2.5 years), 75 patients died and 62 from cardiovascular causes. The prespecified primary and secondary end points considered were total mortality and cardiovascular mortality. No differences between AA, AC, and CC groups were observed with respect to baseline clinical characteristics. Beyond conventional risk factors like age (RR=2.8 [1.6-5.0] 95% CI; p<0.001), hypercholesterolemia (RR=2.1 [1.2-3.7] 95% CI; p<0.014) or low left ventricular ejection fraction (RR=2.7 [1.5-4.8] 95% CI; p<0.002), the AT1R CC genotype was also identified as a strong independent predictor of death after myocardial infarction (RR=3.2 [1.5-7.0] 95% CI ; p<0.004). After adjustment for mortality causes, the AT1R CC genotype was confirmed to be an independent predictor of cardiovascular death after myocardial infarction (RR=2.8 [1.2-6.5] 95% CI; p<0.021). The AT1R CC genotype after adjustment is a strong predictor of death in post MI patients. This new finding may help to identify high risk post MI patients who may benefit from new therapeutic strategies.

Interleukin-10 and tumor necrosis factor gene polymorphisms and risk of coronary artery disease and myocardial infarction

Inflammation plays an important role in the pathogenesis of atherosclerosis and acute coronary syndromes. Cytokines IL-10 and TNF-α exert opposite functions in inflammatory reactions, IL-10 acting predominantly as an antiinflammatory and TNF-α as a proinflammatory factor. Functional single nucleotide polymorphisms in the genes of IL-10, TNF-α, and TNF-β are associated with gene expression and plasma levels of IL-10 and TNF-α. The aim of the study was to assess whether these IL-10 and TNF gene polymorphisms are related to the risk of coronary artery disease (CAD) and myocardial infarction (MI). Consecutive, angiographically examined patients with significant coronary stenoses but without symptoms or signs of old or acute MI constituted the group with CAD ( n=998) and patients with old or acute MI constituted the group with MI ( n=793). Subjects with neither angiographic CAD nor symptoms or signs of MI ( n=340) served as controls. They were matched with the patients for age and sex. Genotyping was performed with techniques based on the polymerase chain reaction. Allele frequencies, genotype distributions, and frequencies of allele combinations for three IL-10 promoter polymorphisms, −1082G/A, −819C/T and −592C/A, were similar between CAD patients, MI patients, and matched controls. Similarly, genetic analysis did not reveal group-specific differences for the TNF-α promoter polymorphisms −863C/A and −308G/A, as well as for the TNF-β intron 1 polymorphism 252G/A. In addition, no relationship was found between specific combinations of IL-10 and TNF alleles, indicative of low IL-10 and high TNF-α production, respectively, and CAD or MI. The lack of association persisted also after adjusting for other cardiovascular risk factors. Our findings suggest that six different and functionally relevant polymorphisms of the genes coding for IL-10, TNF-α, and TNF-β are neither separately nor in cooperation associated with the risk of CAD or MI in angiographically examined patients.

Will more complete inhibition of the RAAS with angiotensin receptor blockade improve survival following myocardial infarction?

Angiotensin-converting enzyme (ACE) inhibitors have a well-established role in the management of patients with hypertension, diabetes, heart failure and myocardial infarction (MI). ACE inhibitors have been particularly well studied in acute and chronic MI with consistent and substantial survival benefits demonstrated, particularly in the higher risk groups. The recent development of angiotensin II (Ang II) receptor blockers (ARBs) as a well tolerated pharmacological therapy to more completely inhibit the actions of Ang II at the AT1-receptor level raises questions concerning comparative efficacy with the proven ACE inhibitor experience. Two major trials will provide a direct comparison of ARBs with an ACE inhibitor. The Valsartan in Acute Myocardial Infarction (VALIANT) trial is specifically designed to compare and contrast the ARB, valsartan, used both alone as well as in combination with a proven ACE inhibitor regimen, in a high risk MI population. VALIANT, with its three arms targetting 14,500 patients, is uniquely poised to determine whether the pharmacological advance in the development of ARBs confers additional clinical (survival) value in high risk MI patients.

ApoA-IV polymorphism associated with myocardial infarction in obese NIDDM patients. The San Luis Valley Diabetes Study.

Non-insulin-dependent diabetes mellitus (NIDDM) confers myocardial infarction (MI) risk unexplained by known factors. In 356 NIDDM patients and 1,087 people with normal glucose tolerance, we investigated the association between MI risk and polymorphism at codon 360 in the apolipoprotein A-IV (apoA-IV) gene. During 1984-1992, MI was diagnosed in 84 diabetic and in 106 nondiabetic people. The risk of MI did not differ by apoA-IV phenotype in nondiabetic people; however, in NIDDM patients, those with the apoA-IV 1-2 phenotype had 2.8 (95% confidence interval: 1.4-5.6) higher MI risk than those with the 1-1 phenotype, adjusting for age, gender, ethnicity, hypertension, smoking, body mass index, fat centrality, and low-density lipoprotein and high-density lipoprotein cholesterol. The risk of MI was particularly high in obese NIDDM patients with the apoA-IV 1-2 phenotype: 5.1 (2.4-11.2) times that in obese apoA-IV 1-1 NIDDM patients and 7.7 (3.6-16.7) times that in lean nondiabetic people. The effect of apoA-IV 1-2 did not appear to be a part of the insulin-resistance syndrome nor was it dependent on diabetes duration or control. One half of the excess MI risk in the diabetic population studied was explained by the apoA-IV 1-2 phenotype. These results indicate that approximately 17% of NIDDM patients have a high MI risk apoA-IV phenotype that is particularly deleterious in obese patients.

The Beta-Blocker Pooling Project (BBPP): subgroup findings from randomized trials in post infarction patients

The objective of the Beta-Blocker Pooling Project (BBPP) was to collect and analyse data from the major long-term secondary prevention trials in order to determine whether there are subsets of post-infarction patients who benefit to a greater or lesser extent from beta-blocker therapy than the average patient population. One-year all-cause mortality data from nine trials involving 13 679 patients were obtained. Overall, mortality was 24% lower in the beta-blocker group compared to the placebo group. However, there was heterogeneity among the results of the trials, which tested seven different beta-blockers. Subgroups with high placebo group mortality (e.g. patients with a history of previous myocardial infarction (MI), angina pectoris, mechanical or electrical complications, and digitalis usage) seemed to benefit particularly from beta-blocker treatment. These findings were consistent in the nine trials. Patients in the lower risk subgroups also appeared to benefit from beta-blockers, but this benefit was smaller in absolute terms and inconsistent across the trials. There was no evidence that treatment outcome was related to gender, baseline level of heart rate or blood pressure, or time of initiation of treatment after hospital admission. In conclusion, the Pooling Project indicates that high risk MI patients, without contraindications to beta-blockers, are the prime candidates for long-term therapy, but the lower risk patients may also receive some benefit.

The Beta-Blocker Pooling Project (BBPP): subgroup findings from randomized trials in post infarction patients

The objective of the Beta-Blocker Pooling Project (BBPP) was to collect and analyse data from the major long-term secondary prevention trials in order to determine whether there are subsets of post-infarction patients who benefit to a greater or lesser extent from beta-blocker therapy than the average patient population. One-year all-cause mortality data from nine trials involving 13 679 patients were obtained. Overall, mortality was 24% lower in the beta-blocker group compared to the placebo group. However, there was heterogeneity among the results of the trials, which tested seven different beta-blockers. Subgroups with high placebo group mortality (e.g. patients with a history of previous myocardial infarction (MI), angina pectoris, mechanical or electrical complications, and digitalis usage) seemed to benefit particularly from beta-blocker treatment. These findings were consistent in the nine trials. Patients in the lower risk subgroups also appeared to benefit from beta-blockers, but this benefit was smaller in absolute terms and inconsistent across the trials. There was no evidence that treatment outcome was related to gender, baseline level of heart rate or blood pressure, or time of initiation of treatment after hospital admission. In conclusion, the Pooling Project indicates that high risk MI patients, without contraindications to beta-blockers, are the prime candidates for long-term therapy, but the lower risk patients may also receive some benefit.

Diagnostic significance for coronary artery disease of abnormal Q waves in the “lateral” electrocardiographic leads

To determine the diagnostic significance for coronary artery disease of abnormally large Q waves in leads I, aVL, V 5 and V 6—the “lateral” electrocardiographic leads—the electrocardiograms of 240 patients who had undergone cardiac catheterization were studied. First, the electrocardiograms of 99 subjects proved normal by cardiac catheterization (group 1) were studied to determine the values of the durations of Q waves in leads I, aVL, V 5 and V 6 that should be exceeded to be considered abnormal. These values were 30, 30, 20 and 25 ms, respectively. Then, 67 patients were identified who had abnormal Q waves in at least 1 of these leads (group 2) and 74 patients with at least 1 angiographic abnormality but without abnormal Q waves in any of these leads (group 3). Group 2 had generally more extensive left ventricular disease and a higher prevalence of anterior, inferior and apical healed myocardial infarction (MI) than group 3. However, compared with group 3, group 2 had lower prevalences of significant narrowing of the coronary arteries that supply the left ventricular lateral wall. Within group 2, abnormal Q waves in leads I and aVL (traditionally designated high lateral MI) were associated with anterior as well as apical MI, and abnormal Q waves in leads V 5 and V 6 (traditionally designated anterolateral MI) were associated with inferior as well as apical MI. Thus, abnormal Q waves in leads I, aVL, V 5 and V 6 tend to reflect apical rather than lateral MI and the term anterolateral MI is especially misleading.