The DD genotype of the angiotensin-converting enzyme gene is associated with increased mortality in idiopathic heart failure

OBJECTIVES: The aim of the present study was to investigate the association between the homozygous DD (deletion) genotype of the angiotensin-converting enzyme gene and survival and cardiac function in patients with idiopathic congestive heart failure. BACKGROUND: The DD genotype gene is a linkage marker for an etiologic mutation at or near the angiotensin-converting enzyme gene and has been associated with increased risk for the development of coronary artery disease, left ventricular hypertrophy and left ventricular dilation after myocardial infarction. We investigated the association between this angiotensin-converting enzyme genotype and mortality in a population-based cohort of patients with idiopathic congestive heart failure. METHODS: The genotype was determined in 193 patients recruited from a large unselected population of patients with congestive heart failure (n = 2,711). The patients were studied with echocardiography, and survival data were obtained after 5 years of follow-up. A control group from the general population (n = 77) was studied by a similar procedure. RESULTS: The frequency of the D allele was not significantly different in the study and control groups (0.57 vs 0.56, p = NS). Long-term survival was significantly worse in the patients with the DD genotype than in the remaining patients (5-year survival rate 49% vs. 72%, p = 0.0011 as assessed by log rank test). The independent importance of the DD genotype for prognosis was verified by a multivariate Cox proportional hazards analysis, by which the odds ratio for mortality and the DD genotype was 1.69 (95% confidence interval 1.01 to 2.82). The only significant difference in cardiac function data between the two groups was an increase in left ventricular mass index in the DD group (153 +/- 57 vs 134 +/- 44 g/m2, p = 0.019). CONCLUSIONS: Angiotensin-converting enzyme gene DD polymorphism was associated with poorer survival and an increase in left ventricular mass in patients with idiopathic heart failure. The results suggest a possible pathophysiologic pathway between angiotensin-converting enzyme gene polymorphism, angiotensin-converting enzyme activity, myocardial hypertrophy and survival. Therefore, the DD genotype may be a marker of poor prognosis in patients with congestive heart failure.     

DD genotype of the angiotensin-converting enzyme gene is a risk factor for left ventricular hypertrophy

BACKGROUND: The cardiac renin-angiotensin system has been suggested to be involved in the development of left ventricular hypertrophy. In humans, a strong correlation has been found between plasma angiotensin I-converting enzyme (ACE) activity and the insertion/deletion (I/D) polymorphism of the ACE gene, which has been reported to be associated with myocardial infarction, ischemic and idiopathic dilated cardiomyopathy, sudden death in hypertrophic cardiomyopathy, and restenosis after percutaneous transluminal coronary angioplasty. In the present study, we examined the possibility that the genotype of the ACE gene might influence the development of left ventricular hypertrophy. METHODS AND RESULTS: The study population consisted of 268 subjects randomly selected from our outpatient clinic. In 142 subjects, left ventricular mass (LVM) was determined by echocardiogram. The genotype of the ACE gene was determined by the polymerase chain reaction. ANCOVA revealed that the genotype of the ACE gene had no effect on blood pressure. The percentage of the explained variance of LVM with variables including diastolic blood pressure (DBP, P = .0001), body mass index (BMI, P = .0001), sex (P = .0009), and the genotype of the ACE gene (P = .0017) was 34.61%. Significant differences in the effects of the genotype of the ACE gene on LVM were observed between the II and DD (P = .0004) and between the ID and DD (P = .0077) genotypes. The percentage of the explained variance of the LVM/ht ratio with variables including sex (P = .134), age (P = .3655), the genotype of the ACE gene (P = .0014), BMI (P = .0001), and DBP (P = .0001) was 31.25%. Significant differences in the effects of the genotype of the ACE gene on LVM/ht were observed between the II and DD genotypes (P = .0003) and between the ID and DD genotypes (P = .0091). CONCLUSIONS: In addition to BMI and DBP, the genotype of the ACE gene was a significant predictor of LVM and LVM/ht in our study population.     

Angiotensin-converting enzyme DD genotype and cardiovascular disease in heterozygous familial hypercholesterolemia

BACKGROUND: Controversy exists as to whether the deletion/deletion genotype (DD) of the ACE gene polymorphism increases the risk of myocardial infarction (MI). Studies have suggested that the ACE DD genotype is associated with increased plaque instability. We hypothesized that the ACE DD genotype may increase the risk of myocardial infarction and coronary heart disease (CHD) in patients with heterozygous familial hypercholesterolemia (FH) or familial defective apolipoprotein B-100 (FDB) who, as a group, are at high risk of having lipid-rich plaques in their coronary arteries. METHODS AND RESULTS: We determined the ACE genotypes and incidence of MI or surgical intervention for CHD in 213 adult patients with heterozygous FH or FDB. The incidence of MI in 35 male patients who carried the ACE DD genotype was 2.5 times that observed in male patients with the II or DI genotypes, and the incidence of CHD in male patients with the DD genotype was 2.2 times higher than in those who had ACE DI+II. The potential effects of ACE genotype on CHD could not be directly compared in female patients because of a disparity in the smoking history of the genotypic groups. From logistic regression analysis, the estimated odds ratio associated with the ACE DD genotype was 2.57 for MI and 2.21 for CHD adjusted for age, sex, and smoking history. CONCLUSIONS: The ACE DD genotype is associated with an increased risk of MI and CHD in patients with heterozygous FH or FDB. Determination of the ACE genotype in asymptomatic FH and FDB patients provides an additional means to identify those patients at greatest risk for the premature development of CHD.     

Long-term prediction of coronary heart disease mortality in two rural Greek populations

In 1960-61 two pooled Greek rural populations totalling 1215 men aged 40-59 years were followed-up for 25 years. A Cox model analysis of fatal coronary events over 15 years showed that serum cholesterol in men aged 40-59 years, cholesterol in men aged 45-64 years, and systolic blood pressure in men aged 50-69 played a predictive role. The coefficient of age became more significant with advancing age and that of cigarette smoking only at 25 years follow-up. The coefficient of cholesterol decreased stepwise and became negative for men aged 50-69; body mass index was without effect in any follow-up of these cohorts. Systolic blood pressure and serum cholesterol increased in these populations by 5.4 mmHg and 23.5 mg.dl-1 (0.61 mmol.l-1), respectively between the years 0 and 10, whereas cigarette consumption decreased minimally. These changes were used to test the predictability of coronary events occurring between years 10 and 25 of follow-up when added to the model containing the factors at entry. Of these changes only systolic blood pressure significantly increased the predictability of coronary deaths. It is concluded that even minor alterations in systolic blood pressure above or below the entry levels can be associated with marked modifications in coronary mortality above or below those occurring naturally in the 15 years after the changes occurred.     

The association of education with coronary heart disease mortality in the USSR Lipid Research Clinics Study

There is a strong inverse association between educational attainment and coronary heart disease (CHD) mortality in men in the USSR Lipid Research Clinics (LRC) Study. Less educated men were characterized by higher mean blood pressure, high density lipoprotein cholesterol (HDL-C), cigarettes smoked and by lower mean low density lipoprotein cholesterol (LDL-C) and body mass index (BMI). With respect to nutritional variables, less educated men were characterized by higher mean energy per kg body weight and alcohol intake and by lower mean intake of fat, saturated, mono- and polyunsaturated fatty acids, cholesterol, sucrose, and other sugars. The Keys score closely predicted the differences in plasma cholesterol among the educational groups in the randomly selected sample. In men without CHD at entry, the age and clinic-adjusted relative risk for CHD mortality was 2.4 for the least educated compared with the most educated group; on adjusting for systolic blood pressure, HDL-C, LDL-C, BMI, alcohol intake and number of cigarettes, the relative risk was reduced to 1.9. These data indicate that only 22% of the twofold excess of CHD mortality associated with low education was statistically attributable to the major risk factors. The failure to explain more of the education-CHD mortality gradient in the USSR LRC cohort was similar to observations from cohort studies in Great Britain and the US. Other correlates of low education must be explored to explain the association.     

Risk factors for coronary heart disease mortality among persons with diabetes

Although synovial lining cells (SLC) have been implicated in the production of hyaluronan (HA), which is found at particularly high concentrations in synovial fluid, the degree to which individual cells within the synovium are adapted to this particular function remains to be elucidated. Uridine diphosphoglucose dehydrogenase (UDPGD) activity is the irreversible, rate-limiting step in the production of UDP-glucuronate, an essential monosaccharide in the synthesis of HA. We have assessed the UDPGD activity, microdensitometrically, in individual lining cells of normal and rheumatoid (RA) synovium, using a modified quantitative cytochemical method. In normal synovium, high activity was confined to the cells of the lining with negligible activity in the deeper subintima. The mean UDPGD activity/cell in lining cells of rheumatoid synovium was significantly lower than the activity in normal SLC. In some samples of RA and normal synovium, a bimodal distribution of cells was evident in the lining on the basis of UDPGD activity, a zone of cells in the basal layers with high UDPGD activity and a separate population of cells in more superficial layers with relatively low UDPGD activity. The results suggest that a particular population of cells is present, consistently in normal and more variably in RA synovial lining, which have high UDPGD activity/cell and may be involved in the production of HA. Furthermore, in RA synovium both the UDPGD activity/cell and the relative proportion of these cells within the lining appear to be decreased.     

Cardiothoracic ratio and relative heart volume as predictors of coronary heart disease mortality. The Whitehall study 25 year follow-up

Searching for an in vitro model for somatic hypermutation, we have identified an IgM-expressing Burkitt lymphoma line that constitutively diversifies its immunoglobulin V domain at high rate during culture. As in in vivo, the mutations are largely nucleotide substitutions with the pattern of substitutions revealing a component of the human hypermutation program that is preferentially targeted to G/C residues. The substitutions frequently create stop codons with IgM-loss variants also being generated by V domain-specific deletions and duplications. However, in transfectants expressing terminal deoxynucleotidyl transferase, many IgM-loss variants additionally arise through short nontemplated nucleotide insertions into the V (but not C) domain. Thus, antibody hypermutation is likely accompanied by DNA strand breaks scattered within the mutation domain.     

Gender differences in use of stress testing and coronary heart disease mortality: a population-based study in Olmsted County, Minnesota

The distribution of CD57+ T and CD56+ T cells in patients with RA was examined. In control osteoarthritis patients, these cells exist as a minor population in the peripheral blood. Our data show that in patients with RA, CD57+ T cell levels are elevated in peripheral blood, knee joint fluid, knee synovial membrane and bone marrow (BM), compared with peripheral blood of controls. CD57+ T cells are especially high in knee joint fluid and joint-adjacent BM, while CD56+ T cells show no such increase. CD57+ T cells contain a major population of CD8+ cells and higher proportions of CD4-8- cells and gammadelta T cells than do CD57- T cells. CD57+ T cells in peripheral blood and joint fluid increase with the duration of disease. Erythrocyte sedimentation rate (ESR) is inversely correlated with the proportion of CD57+ T cells in the joint fluid. Although RA frequently occurs in patients with CD3+57+ cell leukaemia, and some CD57+ T cells are likely to be involved in the onset of RA, we suggest that CD57+ T cells may rather suppress inflammation of RA, and other cellular components (e.g. granulocytes) may govern the severity of the inflammation of RA. These CD57+ T cells are probably generated extrathymically in the adjacent BM or joint space.     

Neighborhood social context and racial differences in women's heart disease mortality

Compared to white women, black women experience similar rates of heart disease morbidity, but higher rates of heart disease mortality. This puzzling relationship may be due to several factors working at varied levels to affect each race. For example, the high heart disease mortality rate may be due to individual health or socioeconomic risk factors or to social structural factors. We conduct a multi-level analysis to address these issues, using data from a newly released data file that links the National Health Interview Survey with death certificate information from the National Death Index, and with additional community level data from the 1990 Census STF-3A files. We are primarily interested in the effects of female-headship rates in the census tracts on coronary heart disease mortality (CHD) among black and white women. We find that women who live in communities with high concentrations of female-headed families are more likely to die of heart disease, net of other characteristics. For younger women, the effect appears to be routed primarily through poverty whereas for older women the effect of female-headship rates remains, net of other census tract characteristics. This study, then, highlights the importance of examining the effect of neighborhoods and their social content on mortality.     

Ethnic differences in coronary heart disease case fatality rates in Auckland

Data from the Auckland Coronary or Stroke (ARCOS) study for the years 1983 to 1992 were analysed to describe 28-day case fatality rates from coronary heart disease among Europeans, Maori and Pacific Islands people in Auckland, New Zealand. The case fatality rate was consistently higher in each age group and for both sexes among Maori and Pacific Islands people than in Europeans. Age-standardised case fatalities for Maori and Pacific Islands people were similar at around 65 per cent, compared with around 45 per cent among Europeans, and these differences were not explained by ethnic differences in possible underreporting of nonfatal myocardial infarction, in socioeconomic status, smoking, symptoms or past myocardial infarction. There was evidence of a more rapid progression of acute coronary events to a fatal outcome among Maori and Pacific Islands people, partly explained by delays in access to life support and coronary care: greater proportions of Pacific Islands people than Maori or Europeans who died did so within an hour of onset of symptoms (56 per cent of Pacific Islands people, 47 per cent of Maori, 45 per cent of Europeans). Pacific Islands and Maori people with acute coronary events took longer to reach a coronary care unit (mean times: Pacific Islands people 8.6 hours, Maori 7.4 hours, Europeans 6.7 hours, P < 0.05), although the median times were not significantly different; life-support units were used by a majority of Pacific Islands people and Europeans (57 per cent and 55 per cent, respectively), compared with only 46 per cent of Maori, but hospital care was similar for the three groups. Further qualitative and quantitative research is needed to investigate the reasons for these ethnic disparities in case fatality rates.     

Sex differences in the impact of coexistent diabetes on survival in patients with coronary heart disease

OBJECTIVE: To evaluate the sex difference in the impact of diabetes on survival in patients with coronary heart disease. RESEARCH DESIGN AND METHODS: Cohort study based on a sample from a hospital registry in Chicago, IL. A total of 974 consecutive patients (585 men and 389 women) with angiographically confirmed coronary artery disease were followed for 4.6 yr. RESULTS: At baseline, 160 men and 155 women had diabetes. The age-adjusted relative risk of death from all causes for patients with diabetes versus patients without diabetes was 0.93 (95% confidence interval 0.65-1.34) in men and 1.99 (95% CI 1.30-3.05) in women. For cardiac death, the corresponding relative risk was 1.00 (95% CI 0.64-1.56) and 1.96 (95% CI 1.19-3.24) in men and women, respectively. Baseline differences in age, hypertension, body mass index, number of diseased vessels, and ejection fraction did not fully explain the excess mortality risk in diabetic women. Excess risk was apparent in both cardiac and noncardiovascular categories. Among nondiabetic patients, the risk of death was significantly lower in women compared with men (multivariate-adjusted relative risk = 0.61, 95% CI 0.41-0.89). However, the mortality risk of diabetic women became similar to men as a whole (relative risk = 1.13, 95% CI 0.80-1.60). CONCLUSIONS: Diabetes confers a substantially higher risk of mortality in women than in men when it occurs in the presence of coronary heart disease.     

Circadian activity of the endogenous fibrinolytic system in stable coronary artery disease: effects of beta-adrenoreceptor blockers and angiotensin-converting enzyme inhibitors

OBJECTIVES: To examine circadian changes in the sympathovagal balance, the activity of the renin-angiotensin system and hemostatic variables in patients with stable coronary artery disease, and the effects of beta-adrenoceptor blockade and angiotensin-converting enzyme inhibition. BACKGROUND: Sympathovagal balance and key components of the fibrinolytic system show circadian variability. The effects of beta-adrenergic blocking agents and angiotensin-converting enzyme inhibitors on these autonomic and hemostatic rhythms are not well defined. METHODS: Twenty patients with coronary artery disease underwent 24-h Holter monitoring for heart rate variability and blood sampling (6 hourly for 24 hours) after three consecutive treatment phases, (firstly with placebo, then bisoprolol, and finally quinapril). The effects on sympathovagal balance, hemostatic variables and the renin-angiotensin system activity were measured. RESULTS: The fibrinolytic capacity showed marked circadian variation at the end of the placebo phase (p = 0.002), plasminogen activator inhibitor-1 (PAI-1) activity peaking at 06.00 AM when tissue plasminogen activator (tPA) activity was at its nadir. Sympathovagal balance showed a sharp increase at approximately the same time but plasma renin activity did not rise until later in the day. Inspection of the 24-h profiles suggested that bisoprolol reduced sympathovagal balance and the morning peak of PAI-1 activity and antigen, with a small increase in tPA activity, although these changes were not significant. Quinapril produced a substantial rise in renin (p = 0.01) but did not significantly affect either PAI-1 or tPA. Sympathovagal balance was unaffected by quinapril. CONCLUSIONS: In patients with stable coronary artery disease, angiotensin-converting enzyme inhibition with quinapril does not affect either sympathovagal balance or the endogenous fibrinolytic system. Our data suggest that the sympathoadrenal system may modify fibrinolytic activity, judged by the response to beta-adrenoreceptor blockade with bisoprolol.     

Enhanced expression of angiotensin-converting enzyme is associated with progression of coronary atherosclerosis in humans

BACKGROUND: The clinical usefulness of angiotensin converting enzyme (ACE) inhibitors in preventing the recurrence of myocardial infarction has been investigated in large randomized trials. Results from many studies using animal models have suggested that ACE inhibitors have vasculoprotective effects, which may contribute to the prevention of coronary atherosclerosis. OBJECTIVE: To examine the association between vascular angiotensin generation and the development of coronary atherosclerosis in humans. METHODS: We used immunocytochemical techniques to examine frozen sections from 44 coronary artery segments from 19 corpses. RESULTS: Three segments were sites of plaque rupture in patients who had died from acute myocardial infarction. Other specimens of coronary artery segments were characterized histologically to be normal artery segments with diffuse intimal thickening (n = 6), hypercellular lesions composed of smooth muscle cells with or without infiltration of macrophages (n = 11), atheromatous plaque (n = 12), and fibrosclerotic plaque (n = 12). In normal arteries with diffuse intimal thickening, ACE was expressed in endothelial cells. In those with hypercellular lesions and atheromatous plaques, however, enhanced ACE expression was found in macrophages and smooth muscle cells. In contrast, arteries with fibrosclerotic plaques exhibited little or no ACE expression within the plaque. All three ruptured plaques expressed ACE strongly in macrophages accumulated around the attenuated fibrous cap. CONCLUSION: The strong association of enhanced ACE expression with the histologic characteristics of plaques suggests that ACE in hypercellular lesions, atheromatous plaques, and ruptured plaques contributes greatly to the further progression of atherosclerosis via an increase in vascular angiotensin II formation and inactivation of bradykinin.     

Abnormal left ventricular filling after neonatal repair of congenital heart disease: association with increased mortality and morbidity

BACKGROUND: The presence of mid-diastolic flow reversal on the mitral valve Doppler inflow indicates abnormal left ventricular filling. To determine whether mid-diastolic flow reversal predicts outcome in patients undergoing repair or palliation of neonatal congenital heart disease, we reviewed the echocardiograms and medical records of 40 patients with either left ventricular outflow obstruction or transposition of the great arteries. METHODS: All patients underwent surgical repair; transposition of the great arteries (TGA) = 17, coarctation of the aorta (CoA) = 14, interrupted aortic arch (IAA) = 8, and aortic stenosis (AS) = 1. The presence of mid-diastolic flow reversal was determined by pulsed Doppler interrogation of the mitral valve on preoperative and postoperative echocardiograms. RESULTS: Preoperative echocardiograms showed diastolic flow reversal in only 5 patients; 1 of 1 with AS and 4 of 14 with CoA. Twenty-one of 40 patients showed postoperative diastolic flow reversal; 1 of 1 with AS, 8 of 8 with IAA, 1 of 14 with CoA, and 11 of 17 with TGA. Postoperative mid-diastolic flow reversal 1 to 3 days after surgery was associated with higher mortality rate: 7 of 21 patients with diastolic flow reversal and 0 of 19 without diastolic flow reversal died. Patients with diastolic flow reversal who survived had longer intensive care unit (26.2 +/- 13.5 days vs 7.1 +/- 4.1 days, P <.001) and hospital (57.4 +/- 38.8 days vs 14.8 +/- 5.2 days, P <.05) stays. CONCLUSION: Mid-diastolic flow reversal is an indicator of prolonged hospital stay and mortality in patients with left ventricular outflow tract obstruction or TGA.     

The clinical efficacy of the first Russian angiotensin-converting enzyme inhibitor methiopril in patients with heart failure

Changes in central hemodynamics as recorded by tetrapolar rheography were investigated in 90 coronary heart disease (CHD) patients with circulatory insufficiency (CI) receiving methiopril. Relevant clinical response was registered in 94%, hemodynamic in 83% of patients. Those with CI stage IIA and IIB benefited more. Arterial pressure went down significantly only in CHD patients with arterial hypertension. Tachycardia patients showed a reduction in pulse rate absent in bradycardia. Cardiac output increased at the expense of low afterload. Efficient doses averaged 300 mg/day.     

Do angiotensin-converting enzyme inhibitors prolong life in patients with heart failure treated in clinical practice?

Angiotensin converting enzyme (ACE) inhibitors have emerged as a significant advance in the treatment of heart failure; yet only a minority (i.e., 30% to 40%) of eligible patients are being treated with these drugs, and even among treated patients, the doses used in clinical practice are substantially lower than those used in the clinical trials that established the efficacy and safety of these agents. The preference for low doses is based on the belief that low and high doses exert similar benefits but that high doses produce more side effects. Yet, most studies indicate that large doses of ACE inhibitors produce greater hemodynamic and clinical effects than small doses, with no additional toxicity. However, it is uncertain whether the survival effects of these drugs are also related to dose. To address this question, a large multinational, double-blind clinical trial (Assessment of Treatment With Lisinopril and Survival [ATLAS]) was launched to compare the effects of low and high doses of the ACE inhibitor lisinopril on the survival of patients with heart failure. If the study demonstrates that large doses are needed to produce optimal effects on mortality, then the low dose strategies that are now widely used in clinical practice may be inadvertently nullifying the enormous potential benefits that ACE inhibitors might otherwise have on public health.