Male Survivors Of Myocardial Infarction Research Articles

How gender-specific are predictors of post-MI HRQoL? A longitudinal study

PurposeExtant research shows that health-related quality of life (HRQoL) differs between female and male survivors of myocardial infarction (MI), but the reasons for this are not fully understood. We aimed to examine the predictors of HRQoL in female and male survivors during the first year after MI.MethodsAt timepoints 1 and 2, the sample comprised 222 MI survivors (59 women and 163 men; mean age 53.84 years, range 24–65) referred for in-patient cardiac rehabilitation. This number dropped to 140 participants (42 women and 98 men) at the third timepoint, approximately one year after the MI. We examined the gender differences in various predictors of physical and mental HRQoL: demographic factors (e.g., age, education, marital status), disease-related factors (pre- and post-MI), personality and coping with stress.ResultsInitially, both physical and mental HRQoL were lower in women than men, but the differences disappeared at timepoint 3. Stepwise regressions performed separately for men and women revealed that the factors shaping HRQoL were different in both genders; they also changed over time. Substantially fewer factors predicted physical HRQoL in women than in men. Trait anxiety seems to play a similarly negative role in both genders.ConclusionsThe psychosocial resources that influence HRQoL were different for women and men. There were also differences concerning predictors of HRQoL dimensions. Further studies with a different or broader range of predictors are needed, especially among women.

Physical Activity and Mortality among Male Survivors of Myocardial Infarction.

An inverse association between physical activity (PA) and risk of CHD has been seen in many studies, but evidence for benefits of PA after myocardial infarction (MI) in reducing mortality is limited. Using data from the Health Professionals Follow-up Study cohort, we followed male survivors of MI. Short- and long-term changes in PA from before to after MI were calculated, and participants without ambulation impairment were classified into maintained low, decreased, increased, or maintained high PA categories. Cox models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for mortality across PA and PA change categories. During a mean of 14 yr of follow-up of 1651 incident nonfatal MI cases, we documented 678 deaths, 307 were due to cardiovascular disease. The adjusted HR for all-cause mortality comparing ≥21 with ≤1.5 MET·wk of PA before MI was 0.73 (95% CI = 0.59-0.89, Ptrend = 0.03). Compared with men who maintained low PA before and after MI, men who maintained high PA had a 39% (95% CI = 25-50) lower risk of all-cause mortality, and those who had a long-term increase in PA from before to after MI had a 27% (95% CI = 6-43) lower risk. Walking for ≥30 min·d after MI was associated with a 29% lower mortality (HR = 0.71, 95% CI = 0.58-0.84), independent of walking pace, and walking pace after MI was inversely associated with mortality (HR = 0.67, 95% CI = 0.49-0.92). Maintaining a high PA or having a long-term increase in PA from before to after MI was associated with lower mortality among male MI survivors. Walking time and walking pace after MI were each inversely associated with mortality.

Proteolytic and genetic variation of the alpha-2-antiplasmin C-terminus in myocardial infarction

AbstractAlpha-2-antiplasmin (α2AP) undergoes both N- and C-terminal cleavages, which significantly modify its activities. Compared with other Ser protease inhibitors (serpins), α2AP contains an ∼ 50-residue–extended C-terminus, which binds plasmin(ogen). We developed 2 new ELISAs to measure the antigen levels of free total α2AP and free C-terminally intact α2AP to investigate whether α2AP antigen levels or α2AP C-terminal cleavage were associated with myocardial infarction (MI) in 320 male MI survivors and 169 age-matched controls. Patients had 15.2% reduced total α2AP antigen levels compared with controls (93.8 vs 110.6 U/dL, P < .001), with a 10.1-fold (95% confidence interval [CI]: 5.5-18.9) increased MI risk for levels in the 1st quartile compared with the 4th quartile. The percentage of C-terminal cleavage did not differ between patients and controls (38.7% and 38.1%, respectively, P = .44). In addition, all individuals were genotyped for the polymorphism Arg407Lys, which is located near the start of the extended C-terminus. Arg407Lys was not associated with α2AP C-terminal cleavage, total α2AP antigen levels, or MI risk (odds ratios compared with Arg/Arg: Arg/Lys 0.74, 95% CI: 0.50-1.10; Lys/Lys 0.77, 95% CI: 0.31-1.92). Our data show that levels of free full-length α2AP were decreased in MI, that the percentage of C-terminally cleaved α2AP was unaltered, and that Arg407Lys did not influence α2AP levels or MI risk.

Complement C3 and C-reactive protein in male survivors of myocardial infarction

Background Inflammatory processes play a fundamental role in the development of cardiovascular disease. Objectives To compare the associations of complement C3 and C-reactive protein (CRP) with myocardial infarction (MI) and cardiovascular risk factors. Methods 342 Caucasian male subjects aged ≤65 years with MI and 193 Caucasian age matched healthy male control subjects were recruited. C3 and CRP were measured by ELISA. Results C3 and CRP were significantly higher ( p < 0.001) in patients compared with healthy subjects (patients vs. healthy subjects, C3: 1.22 g L −1 vs. 1.00 g L −1; CRP: 1.41 mg L −1 vs. 0.72 mg L −1). In a logistic regression model, including conventional cardiovascular risk factors, C3 was independently associated with MI (odds ratio for a 1 S.D. increase in C3: 2.29 [1.58, 2.92]); and this association remained after including CRP and/or fibrinogen in the model. CRP was independently associated with MI after accounting for conventional risk factors (odds ratio for a 1 S.D. increase in CRP: 1.47 [1.16, 1.87]), however, this association was lost when C3 and/or fibrinogen were included in the model. Receiver operating characteristic (ROC) analysis indicated that the model which best predicted MI was the model including C3 and fibrinogen. Conclusions These data suggest that elevated C3 is independently associated with MI and that elevated C3 may be a more specific marker of the inflammatory processes underpinning MI than CRP.

Aggregation of lipoprotein and inflammatory parameters in families with a history of premature myocardial infarction: the Tallinn Myocardial Infarction Study

The offspring of individuals with a history of premature myocardial infarction are at increased risk of premature coronary attacks. The aim of this study was to determine parent/offspring associations of coronary risk factors in families affected by premature myocardial infarction and to compare these to corresponding control families. The cohort of cases consisted of 71 male survivors of myocardial infarction and their 128 descendants (aged 7-18 years). As control families, 85 randomly selected healthy males with their 66 descendants were investigated. Besides traditional risk factors, serum high sensitive C-reactive protein (hsCRP), apolipoprotein (apo) E phenotypes and lipoprotein(a) were analyzed. In the offspring of the patients, fibrinogen and atherogenic lipoprotein parameters were higher than in the corresponding controls, but hsCRP, lipoprotein(a) and anthropometric data did not differ between the groups. The adult-offspring positive correlations were detected in fibrinogen and in almost all measured lipoprotein fractions in the affected families; amongst the controls, the association was observed only for triglyceride levels. Multiple logistic regression analysis demonstrated independent association of offspring apoB, apoA-I and fibrinogen levels with a family history of premature myocardial infarction. The most informative predictors of future coronary attacks during childhood are apoB-100 and apoB/apoA-I ratio; serum hsCRP and lipoprotein(a) do not have predictive value in childhood.

A functional Sp1/Egr1‐tandem repeat polymorphism in the 5‐lipoxygenase gene is not associated with myocardial infarction

Arachidonate 5-lipoxygenase is an enzyme encoded by the ALOX5 gene, and plays an important role in the synthesis of leukotrienes. These are inflammatory mediators, and have been involved in atherosclerosis and other pathological processes that require proinflammatory activities. Human and animal studies have suggested a role for the ALOX5 gene in atherosclerosis, including a significant association between a promoter polymorphism and a carotid intimal-medial thickness in response to dietary fat. This polymorphism was three- to six-tandem repeats of a Sp1/Egr1 binding motif (GGGCGG)(n), and the number of repeats has been linked with the amount of gene expression. We hypothesized that this ALOX5 polymorphism could influence the risk for myocardial infarction (MI). First, we analysed the effect of the four alleles on gene expression by transfecting the HEK-293 cell line with luciferase reporter-constructs. We found that luciferase activities are dependent on the number of the Sp1/Egr1 repeats, with the three and six repeats having the lowest and highest values. We genotyped 312 male MI survivors, aged < 55 years, and 376 healthy controls matched with patients for sex, age, and ethnicity. Ninety-six per cent of the patients were smokers, compared to only 42% among the controls (P < 0.001; OR = 31.84). The 55 + 56 repeat genotypes were less frequent in patients (55 = 56%, 56 = 0.6%) compared to controls (55 = 60%, 56 = 3%). However, these were non-significantly different frequencies. In addition, no difference in MI-onset age and biochemical values was found between the allele and genotypes. In conclusion, we confirmed the effect of the ALOX5-promoter polymorphism on gene expression, but our data did not support a significant effect of this functional variation on MI risk.

Exercise After Myocardial Infarction Improves Contractility and Decreases Myofilament Ca 2+ Sensitivity

See related article, pages 1079–1088 While myocardial infarction (MI) is the major cause of heart failure, there are conflicting data over the roles of abnormal calcium handling and myofilament function. The acute injury leads to the activation of neurohormones and cytokines, subsequent myocardial remodelling, further decline in heart function, and finally overt heart failure. Depressed myocyte contractility in the remodelled myocardium can largely be explained by Ca2+ handling abnormalities.1 Abnormalities in myofilament function are less well understood. A seminal study in pigs demonstrated that impaired pump function three weeks after MI can also be attributed to decreased maximal isometric tension in skinned cardiomyocytes in areas remote from the ischemic border zone.2 Somewhat paradoxically, the impairment occurred in the context of increased Ca2+ sensitivity of the myofilaments. The authors attributed the increased Ca2+ sensitivity following MI to reduced protein kinase A-mediated troponin I (TnI) phosphorylation.2 Increased myofilament Ca2+ sensitivity has also been reported for end-stage human heart failure, apparently largely because of a reduction of TnI phosphorylation.3 One of the most effective and least expensive therapies for cardiovascular disease is exercise. Clinical studies generally show a benefit of exercise training and a reduction of cardiac mortality after MI by 26%.4 The question remains of how soon to start exercising, especially after a large MI. In several clinical5 and animal6,7 studies, there were detrimental consequences when exercise began immediately after an MI. In the current issue of Circulation Research , de Waard et al8 present remarkable data addressing the question of exercise training early post MI. After a large MI, mice were subjected to 8 weeks of “voluntary” exercise training. Exercise had no detrimental effects on mortality and minimal effects on myocardial hypertrophy and left ventricular remodelling. Furthermore, there …

ABCA1 polymorphisms and prognosis after myocardial infarction in young patients

High-density cholesterol (HDL) levels are affected by genetic influences and certain behaviors. Low levels of HDL-C are considered as an independent risk factor for premature coronary heart disease. In patients with Tangier disease, characterised by low HDL levels, mutations in the ATP binding cassette transporter have been described. We have analysed three polymorphisms of the ABCA1 gene (-477C/T, R219 K, and I883M) in a cohort of young male survivors of myocardial infarction in order to know their influence in long-term prognosis. In premature heart disease, knowing prognosis factors is specially relevant.

Relationship between bone mineral density and myocardial infarction in US adults

Cardiovascular disease and osteoporosis have several common risk factors, and quite a few studies suggest a relationship between them. The objective of the present study was to explore the relationship between cardiovascular disease risk factors and bone mineral density in association with having had a previous myocardial infarction in a general population. This cross-sectional study was conducted using data for 5,050 women and men aged 50-79 years who participated in the Third National Health and Nutrition Examination Survey (NHANES III). Race/ethnic and gender-specific mean BMD values for young adults were used to determine race/ethnic and gender-specific T-scores to define osteoporosis and low BMD. Multiple logistic regression analysis revealed that subjects self-reporting a previous myocardial infarction had significantly higher odds (odds ratio 1.28, [95% confidence interval (CI), 1.01 to 1.63] p=0.04) of having low bone mineral density, when adjusting for cardiovascular disease and osteoporosis risk factors. Self-reported myocardial infarction was not significantly associated with low bone mineral density in women, (odds ratio 1.22, [95% CI, 0.80 to 1.86] p=0.37), but was significant in men, (odds ratio 1.39, [95% CI, 1.03 to 1.87] p=0.03). These findings demonstrate that male survivors of myocardial infarction have low bone mineral density. The pathophysiologic connection between the atherosclerotic and the osteoporotic processes needs further elucidation. It is also of importance to study the processes in both men and women.

Exploiting the Vascular Protective Effects of High-Density Lipoprotein and Its Apolipoproteins

“ An invasion of armies can be resisted but not an idea whose time has come.” —Victor Hugo. Vaso-occlusive disease resulting from atherosclerosis and thrombosis is the leading cause of death and morbidity in the United States and other industrialized nations. Although the precise cause of atherosclerosis is unclear, an emerging paradigm suggests that atherosclerosis involves multiple pathways in which lipoprotein entry and retention, injury to the vessel wall from diverse stimuli, and an associated long-term inflammatory and immune response seem to play a key role.1–4 Dyslipidemia characterized predominantly by elevated levels of one or more circulating non-HDL cholesterol lipoproteins [LDL, VLDL, lipoprotein(a), triglycerides] and/or reduced HDL cholesterol is one of the key risk factors for atherosclerosis and cardiovascular disease.5–16 Over the past several years, a number of large, prospective, randomized, controlled clinical trials have demonstrated both angiographic and clinical benefits of lipid-lowering therapy, with a significant reduction in fatal and nonfatal cardiovascular events.17–23 These studies have primarily targeted LDL cholesterol through pharmacotherapy (mostly statins), with or without dietary counseling, lifestyle modification, or surgery (intestinal bypass in Program on the Surgical Control of the Hyperlipidemias [POSCH] trial). Overall, a significant and clinically worthwhile relative risk reduction ranging from 20% to 40% in major cardiovascular events has been achieved with these strategies, without significant adverse effects or increased noncardiovascular mortality. These remarkable results prompted Brown and Goldstein24 to predict that heart attacks will be gone with the century. This clearly reflects an overoptimistic point of view, because 60% to 70% of adverse cardiovascular events continue to occur despite LDL-lowering therapy. Potential reasons why cardiovascular events may continue to occur despite low LDL levels or despite LDL-lowering therapy include the following: (1) we may not be lowering LDL cholesterol to optimal levels, because optimal levels are not clearly …

Atherogenic lipoprotein profile in families with and without history of early myocardial infarction

In this study we compared several parameters characterizing differences in the lipoprotein profile between members of families with a positive or negative family history of coronary artery disease (CAD). In addition to regular parameters such as the body mass index (BMI), total plasma cholesterol (TC), low density (LDL-C) and high density (HDL-C) cholesterol and triglycerides (TG) we estimated the fractional esterification rate of cholesterol in apoB lipoprotein-depleted plasma (FERHDL) which reflects HDL and LDL particle size distribution. A prevalence of smaller particles for the atherogenic profile of plasma lipoproteins is typical. Log (TG/HDL-C) as a newly established atherogenic index of plasma (AIP) was calculated and correlated with other parameters. The cohort in the study consisted of 29 young (&lt; 54 years old) male survivors of myocardial infarction (MI), their spouses and at least one offspring (MI group; n=116). The control group consisted of 29 apparently healthy men with no family history of premature CAD in three generations, their spouses and at least one offspring (control group; n=124). MI families had significantly higher BMI than the controls, with the exception of spouses. Plasma TC did not significantly differ between MI and the controls. MI spouses had significantly higher TG. Higher LDL-C had MI survivors only, while lower HDL-C had both MI survivors and their spouses compared to the controls. FERHDL was significantly higher in all the MI subgroups (probands 25.85±1.22, spouses 21.55±2.05, their daughters 16.93±1.18 and sons 19.05±1.33 %/h) compared to their respective controls (men 20.80±1.52, spouses 14.70±0.98, daughters 13.23±0.74, sons 15.7±0.76 %/h, p&lt;0.01 to p&lt;0.05). Log (TG/HDL-C) ranged from negative values in control subjects to positive values in MI probands. High correlation between FERHDL and Log (TG/HDL-C) (r = 0.80, p&lt;0.0001) confirmed close interactions among TG, HDL-C and cholesterol esterification rate. The finding of significantly higher values of FERHDL and Log (TG/HDL-C) indicate higher incidence of atherogenic lipoprotein phenotype in members of MI families. The possibility that, in addition to genetic factors, a shared environment likely contributes to the familial aggregation of CAD risk factors is supported by a significant correlation of the FERHDL values within spousal pairs (control pairs: r = 0.51 p&lt;0.01, MI pairs: r = 0.41 p&lt;0.05).

Risk factors for atherosclerosis in survivors of myocardial infarction and their spouses: Comparison with spousal pairs without personal and family history of atherosclerosis

To explore the hypothesis that an interplay between genetic and environmental factors contributes to the development of coronary atherosclerosis, we compared the prevalence of risk factors for atherosclerosis among survivors of myocardial infarction (MI) and their spouses and apparently healthy men and women (spousal pairs) with no personal and family history of atherosclerosis in three generations. There were no significant differences in life-style and dietary habits between the groups. The daily vegetable and/or fruit intake was generally low and did not differ between the groups. Thirty percent and 25% of men and women did not consume any vegetables or fruits, respectively. All differences found in the male MI survivors and control men were also found between the female groups: MI survivors and their spouses were significantly more obese and had higher systolic and diastolic blood pressure and more pathologic plasma lipid levels compared with control males and females, respectively. Compared with the control men and women, MI survivors and spouses had higher plasma homocysteine (Hcy) levels (15.3 6 10.5, 11.9 6 4.0, 16.9 6 5.5, and 14.3 6 4.0, mmol/L, respectively, P 5 .01). The frequency of the homozygous C677T 5,10-methylenetetrahydrofolate reductase (MTHFR) polymorphism in MI survivors was twice that observed in their spouses and controls (12.1%, 4.8%, and 5.8%, respectively), but this difference did not reach statistical significance. A statistically significant association of the MTHFR genotype and Hcy concentration (multiple ANOVA) was shown. Neither the frequencies of apolipoprotein E (apoE) alleles nor Asp9Asn mutation of exon 2, Asn291Ser mutation of exon 6, and Ser447Ter of exon 9 of the lipoprotein lipase (LPL) gene varied significantly among the groups. A possible explanation for our findings is that individuals with a genetic predisposition for atherosclerosis and their spouses share a life-style that results in a higher body mass index (BMI) and waist to hip ratio (WHR). On the other hand, individuals with no family history of atherosclerosis, despite an unhealthy life-style similar to that in the affected families (diet and physical activity), had a lower BMI and WHR and more favorable metabolic parameters, including plasma Hcy. In conclusion, we have shown that a personal and/or family history of atherosclerosis corresponds to the prevalence and level of risk factors for atherosclerosis. A combination of life-style factors and inherited metabolic abnormalities, including high plasma Hcy, are the more likely explanation for our findings. Copyright © 2001 by W.B. Saunders Company

Serum insulin-like growth factor-I level is independently associated with coronary artery disease progression in young male survivors of myocardial infarction: beneficial effects of bezafibrate treatment

OBJECTIVESWe investigated whether the effect of bezafibrate on progression of coronary atherosclerosis in the BEzafibrate Coronary Atherosclerosis Intervention Trial (BECAIT) was related to insulin-like growth factor (IGF)-I and glucose-insulin homeostasis.BACKGROUNDBECAIT, the first double-blind, placebo-controlled, randomized, serial angiographic trial of a fibrate compound, demonstrated that progression of focal coronary atherosclerosis in young patients after infarction could be retarded by bezafibrate treatment.METHODSThe treatment effects on serum concentrations of IGF-I and insulin-like growth factor binding protein (IGFBP)-1, as well as on basal and postload glucose and insulin levels, were examined, and on-trial determinations were related to the angiographic outcome measurements.RESULTSBezafibrate treatment resulted in a significant reduction of serum IGF-I levels, both at two and five years, and on-trial serum IGF-I levels were directly related to changes in both minimal lumen diameter (r = 0.25, p < 0.05) and mean segment diameter (r = 0.29, p < 0.05). In contrast, none of the available indexes of insulin resistance (homeostasis model assessment estimate, basal and postload plasma insulin concentrations and serum IGFBP-1 levels) were related to the angiographic changes, nor were they significantly affected by bezafibrate treatment. Multiple stepwise regression analysis showed that the relation between on-trial serum IGF-I level and coronary artery disease (CAD) progression was independent of baseline angiographic score, age, body mass index, serum lipoprotein and plasma fibrinogen concentrations and measures of glucose–insulin homeostasis.CONCLUSIONSIGF-I could be implicated in the progression of premature CAD, and a reduction of serum IGF-I concentration could account partly for the effect of bezafibrate on progression of focal coronary atherosclerosis.

Elevated Chlamydia pneumoniae Antibodies, Cardiovascular Events, and Azithromycin in Male Survivors of Myocardial Infarction

Fischer, Staci A.; Gupta, S; Leatham, E W; Carrington, D; Mendall, M A; Kaski, J C; Camm, A J Author Information

Bezafibrate following acute myocardial infarction: important findings from the bezafibrate coronary atherosclerosis intervention trial

Summary Objective : The study was designed to assess whether bezafibrate could retard or prevent the progression of atherosclerotic lesions in young male survivors of myocardial infarction. Design : The study was of a randomized, parallel group double-blind design. Setting : Patients were recruited into the trial from the ten hospitals in Stockholm County. Interventions : After 3 months diet, patients who fulfilled the entry criteria were randomized to treatment with bezafibrate (200 mg tid), or placebo, for 5 years. Diet was continued throughout the trial. Main outcome measures : Quantitative computer assisted coronary angiography was undertaken at baseline and after 2 and 5 years, blood lipids were assessed every 4 months, and plasma fibrinogen was monitored before treatment, at 2 and 5 years. Results : Progression as assessed by mean minimum lumen diameter (MLD) was less in the bezafibrate group then in the placebo group. The treatment effect was +0.13 mm for the primary endpoint MLD ( P = 0.049). Supportive parallel treatment effects, although not reaching statistical significance, were observed for the secondary angiographic endpoints: mean segment diameter +0.02 mm and percent stenosis −3.41%. There was a significantly lower cumulative coronary event rate amongs patientst treated with bezafibrate (3 vs. 11: P = 0.019). The angiographic effects of bezafibrate were accompanied by statistically significant treatment effects for serum cholesterol (−9%), VLDL-cholesterol (−35%), serum triglycerides (−31%), VLDL-triglycerides (−37%), and plasma fibrinogen levels (−12%). There was no net change in LDL-cholesterol and HDL-cholesterol increased significantly by 9%. Conclusions : By correcting the underlying dyslipidaemia and the haemostatic imbalance, bezafibrate is able to slow the progression of coronary atherosclerosis in a group of young post-myocardial infarction patients.

Retardation of coronary atherosclerosis: the Bezafibrate Coronary Atherosclerosis Intervention Trial (BECAIT) and other angiographic trials.

A large number of both primary and secondary preventive trials suggest that treatment of elevated plasma lipids may reduce the frequency of coronary heart disease (CHD) events. Meta-analyses indicate that for every 10% reduction of cholesterol, CHD mortality is lowered by 13% and all-cause mortality by 10%. Experience from several angiographic trials also suggests that coronary atherosclerosis can be retarded, and in some instances limited regression induced, by low-density lipoprotein (LDL)-cholesterol reduction and/or high-density lipoprotein (HDL)-cholesterol elevation. Coronary angiographic studies have shown that although the effects on retardation/regression of altherogenic lesions have been small, with luminal diameter changes of around 0.10 mm, the effects on clinical events were more substantial, with reductions of the order of 50%. There is also evidence that it is the mild and moderate lesions that are of particular concern with respect to the occurrence of clinical coronary events. The progression of atherosclerosis and the occurrence of coronary events are probably not exclusively dependent on a lowering of LDL-cholesterol concentrations. Analyses from the Monitored Atherosclerosis Regression Study (MARS), the Cholesterol Lowering Atherosclerotic Study (CLAS), and the Programs on the Surgical Control of the Hyperlipidaemias (POSCH) indicate that triglyceride-rich lipoproteins may also be of importance for the progression of mild/moderate lesions in subjects treated with cholesterol-lowering regimens. Recently, the results of the 5-year Bezafibrate Coronary Atherosclerosis Intervention Trial (BECAIT) demonstrated that bezafibrate significantly retarded the progression of coronary atheroma and coronary events in young male survivors of myocardial infarction, as assessed by changes in minimum lumen diameter. This positive outcome is most likely due to the beneficial treatment effects on the levels of serum triglycerides (-31%), plasma fibrinogen (-12%), and HDL cholesterol (+9%). The results of the BECAIT on progression of coronary atherosclerosis are comparable with those of two recent angiographic trials with HMG-CoA reductase inhibitors, the Multicenter Anti-Atheroma Study (MAAS), and the Regression Growth Evaluation Statin Study (REGRESS), despite different lipid and metabolic effects. BECAIT is the first controlled angiographic study to show that a fibrate can significantly retard the progression of coronary atherosclerosis. The exact mechanisms by which this occurs remain to be elucidated. However, the results of BECAIT illustrate the importance of factors other than LDL cholesterol in the progression of coronary atherosclerosis.

Plasma protein C inhibitor is elevated in survivors of myocardial infarction.

Many studies have shown alterations of the hemostatic and fibrinolytic systems in patients with atherosclerotic disease, principally in levels of plasminogen activator inhibitor-1. However, in a large prospective study only fibrinogen, von Willebrand factor antigen, and tissue plasminogen activator antigen were found to be independent risk markers for acute coronary events. The present study evaluated the fibrinolytic system in coronary artery disease, paying particular attention to another inhibitor of fibrinolysis, plasminogen activator inhibitor-3, also called protein C inhibitor (PCI). One hundred fifteen nonanticoagulated male survivors of myocardial infarction were investigated for a range of hemostatic and fibrinolytic parameters that were compared with values in 87 age-matched healthy control male subjects. PCI active antigen was significantly (P < .03) elevated in the myocardial infarction group compared with the control group and was associated with the number of acute coronary events suffered (P = .005) but not with the severity of disease as determined by coronary angiography. Elevated PCI plasma levels can be considered as a risk marker for acute coronary events and might be of particular importance in the pathogenesis of this disease due to the interference of PCI in both the anticoagulant and fibrinolytic systems.

Bezafibrate. An update of its pharmacology and use in the management of dyslipidaemia.

The lipid-modifying profile of bezafibrate is characterised by marked decreases in elevated triglyceride levels, increases in high density lipoprotein (HDL) cholesterol levels and decreases in total and low density lipoprotein (LDL) cholesterol levels. Bezafibrate also reduces elevated levels of lipoprotein(a) [Lp(a)] and fibrinogen, which are independent cardiovascular risk factors. Bezafibrate is effective in most types of primary and secondary dyslipidaemia. It is of greatest benefit in conditions featuring hypertriglyceridaemia and/or HDL cholesterol deficiency. This is particularly true for patients with diabetes mellitus, notably those with non-insulin-dependent diabetes mellitus (NIDDM) who are also likely to have increased fibrinogen levels. In the limited comparisons available, there appear to be few consistent differences in lipid-modifying effects between bezafibrate and other fibrates. Compared with HMG-CoA reductase inhibitors, bezafibrate causes larger changes in triglyceride and, in general, HDL cholesterol levels, and has a lesser influence on LDL and total cholesterol levels. These differences are advantageous when bezafibrate and HMG-CoA reductase inhibitors are used as combined therapy in patients with severe dyslipidaemia unresponsive to either modality alone. The combination of bezafibrate plus an HMG-CoA reductase inhibitor in clinical trials has not led to the predicted increase in myalgia. Indeed, bezafibrate is generally free of serious unwanted effects: rhabdomyolysis is rare and has occurred mainly in patients with renal dysfunction given excessive dosages. Other patient groups in whom bezafibrate has improved serum lipid profiles are those with isolated HDL cholesterol deficiency, dyslipidaemia secondary to renal insufficiency, and following cardiac surgery or other procedures. However, data for these indications are not extensive. Evidence is now available to show a beneficial effect of bezafibrate on retarding atherosclerotic processes and in reducing risk of coronary heart disease. The 5-year Bezafibrate Coronary Atherosclerosis Intervention Trial (BECAIT) in young male survivors of myocardial infarction demonstrated a smaller decrease in luminal diameter and a reduction in coronary events with bezafibrate compared with placebo. The Bezafibrate Infarction Prevention (BIP) study is expected to provide mortality data which is currently lacking for bezafibrate. In conclusion, bezafibrate is a useful and well-tolerated lipid-modifying agent in the management of primary and secondary dyslipidaemia. It has particularly beneficial effects in patients with hypertriglyceridaemia and/or low HDL cholesterol levels, and reduces fibrinogen levels. Together with its ability to sustain or improve glycaemic control, these properties make it a logical choice for treating patients with diabetes mellitus and dyslipidaemia. Additionally, the drug may be of value as combination therapy in patients with severe dyslipidaemia. Importantly, there is evidence that the drug can slow the atherosclerotic process and reduce cardiovascular morbidity. The ongoing BIP secondary intervention study and other investigations will help clarify the effects of bezafibrate on cardiovascular mortality and morbidity.

Angiographic assessment of effects of bezafibrate on progression of coronary artery disease in young male postinfarction patients

Summary Background Bezafibrate has effects on lipid metabolism and haemostatic function. We undertook a double-blind, placebo-controlled intervention trial, the Bezafibrate Coronary Atherosclerosis Intervention Trial (BECAIT), to establish whether bezafibrate (200 mg three times daily) could retard or prevent the progression of atherosclerotic lesions in dyslipidaemic male survivors of myocardial infarction who were younger than 45 years at the time of the event. Methods 92 patients completed an initial 3-month period of dietary intervention and were randomly assigned to treatment with bezafibrate or placebo. Dietary intervention continued throughout the trial. Coronary angiography was done at baseline and after 2 and 5 years. 81 patients (42 bezafibrate treated and 39 placebo treated) who underwent baseline angiography and at least one posttreatment angiogram were included in the efficacy analysis. The primary endpoint was change in mean minimum lumen diameter. Findings The mean minimum lumen diameter decreased from baseline to the last angiographic assessment (2 or 5 years) by 0·06 mm (95% Cl 0·15 reduction to 0·01 increase) in the bezafibrate group and by 0·17 mm (0·33 reduction to 0·09 increase) in the placebo group. The treatment effect was therefore 0·13 mm (95% Cl 0·10 to 0·15; p=0·049). Parallel treatment effects, although not statistically significant, were observed for the secondary angiographic endpoints (mean segment diameter 0·02 mm [0·01-0·04] and percentage stenosis -3·41% [-4·00 to -2·98]). The cumulative coronary event rate was significantly lower among bezafibrate-treated than among placebo-treated patients (three vs 11 patients; p=0·02). There were significant treatment effects of bezafibrate for serum concentrations of cholesterol (-9%; p<0·001), very-low-density-lipoprotein (VLDL) cholesterol (-35%; p<0·001), serum triglycerides (-31%; p<0·001), VLDL triglycerides (-37%; p<0·001), and plasma fibrinogen (-12%; p=0·001), whereas low-density (LDL) cholesterol concentrations did not change. High density lipoprotein (HDL) cholesterol increased significantly with bezafibrate (9%; p=0·02). Interpretation The results show that bezafibrate improves dyslipidaemia, lowers plasma fibrinogen, slows the progression of focal coronary atherosclerosis, and reduces coronary events in young survivors of myocardial infarction.

Insulin, Intact and Split Proinsulin, and Coronary Artery Disease in Young Men

Glucose intolerance and hyperinsulinemia are common disturbances in nondiabetic men with premature coronary artery disease (CAD). To investigate the relation between insulin-like molecules and severity of coronary atherosclerosis, 62 consecutive nondiabetic men presenting with a first myocardial infarction before the age of 45 were studied along with 41 healthy, age-matched, male, population-based control subjects. Specific two-site immunoradiometric assays were used to distinguish intact proinsulin, (des 31,32) proinsulin, and "true" insulin in fasting plasma and during an oral glucose tolerance test (OGTT). Global coronary atherosclerosis and number and severity of distinct stenoses were determined in the patients in 15 proximal coronary arterial segments by use of separate semiquantitative classification systems. The patients had a two- to threefold increase in insulin and insulin propeptide concentrations in the fasting state as well as during the OGTT. Severity of coronary atherosclerosis correlated significantly (P < .05 to P < .01) with basal proinsulin (r = .40) and the proinsulin area under the curve (AUC) (r = .34), basal insulin (r = .31), basal C peptide (r = .30), and the glucose AUC (r = .30). In multiple stepwise regression analysis including insulin-like molecules, major plasma lipoproteins, and lipoprotein subfractions, basal proinsulin (increase in R2 = .09) and dense LDL triglycerides (increase in R2 = .10) predicted 19% of the variation of the global coronary atherosclerosis score after adjustment for age, body mass index, fasting insulin concentration, and VLDL triglycerides. This study shows that young, nondiabetic, male survivors of myocardial infarction are truly hyperinsulinemic during an OGTT and suggests a close association between proinsulin and coronary atherosclerosis.