Telomere length loss due to smoking and metabolic traits.

OBJECTIVES: Human age-dependent telomere attrition and telomere shortening are associated with several age-associated diseases and poorer overall survival. The aim of this study was to determine longitudinal leucocyte telomere length dynamics and identify factors associated with temporal changes in telomere length. DESIGN AND METHODS: Leucocyte telomere length was measured by quantitative polymerase chain reaction in 8074 participants from the Prevention of Renal and Vascular End-stage Disease (PREVEND) study, an ongoing community-based prospective cohort study initiated in 1997. Follow-up data were available at two time-points up to 2007. Leucocyte telomere length was measured, on between one and three separate occasions, in a total of 16 783 DNA samples. Multilevel growth models were created to identify the factors that influence leucocyte telomere dynamics. RESULTS: We observed an average attrition rate of 0.47 ± 0.16 relative telomere length units (RTLUs) per year in the study population aged 48 (range 39-60) years at baseline. Annual telomere attrition rate increased with age (P < 0.001) and was faster on average in men than in women (P for interaction 0.043). The major independent factors determining telomere attrition rate were active smoking (approximately tripled the loss of RTLU per year, P < 0.0001) and multiple traits of the metabolic syndrome (waist-hip ratio, P = 0.007; blood glucose level, P = 0.045, and HDL cholesterol level, P < 0.001). CONCLUSIONS: Smoking and variables linked to the metabolic syndrome are modifiable lifestyle factors that accelerate telomere attrition in humans. The higher rate of cellular ageing may mediate the link between smoking and the metabolic syndrome to an increased risk of several age-associated diseases.

The fibrosis marker galectin-3 and outcome in the general population.

OBJECTIVE: Galectin-3 is involved in fibrosis and inflammation and plays a role in heart failure, renal disease, obesity and cancer. We aimed to establish the relationship between galectin-3 and cardiovascular (CV) risk factors and mortality in the general population. DESIGN AND SUBJECTS: This study included 7968 subjects from the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) cohort, with a median follow-up of approximately 10 years. Plasma galectin-3 was measured in baseline samples. MAIN OUTCOME MEASURES: We investigated the relationships between galectin-3 levels, demographic characteristics and risk factors of CV disease. We determined the prognostic value for all-cause, CV and cancer mortality. RESULTS: The mean age of the population was 50 ± 13 years. Mean blood pressure was 129/74 mmHg, mean cholesterol was 5.7 ± 1.1 mmol L(-1) and median galectin-3 was 10.9 ng mL(-1) [interquartile range (IQR) 9.0-13.1]. Galectin-3 levels correlated with a wide range of risk factors of CV disease, including blood pressure, serum lipids, body mass index, renal function and N-terminal pro-B-type natriuretic peptide (P < 0.0001). We observed a strong association between galectin-3 and age. Furthermore, we found a gender interaction, with female subjects (n = 4001) having higher median galectin-3 levels (11.0 ng mL(-1) , IQR 9.1-13.4 vs. men (n = 3967) 10.7 ng mL(-1) , IQR 8.9-12.8; P < 0.0001), and galectin-3 levels in women more strongly correlated with risk factors of CV disease. After correction for the classical CV risk factors (smoking, blood pressure, cholesterol and diabetes), galectin-3 levels independently predicted all-cause mortality (hazard ratio per SD galectin-3 1.09, 95% CI 1.01-1.19; P = 0.036), but not CV and cancer mortality separately. CONCLUSIONS: Galectin-3 is associated with age and risk factors of CV disease, with a strong gender interaction for these correlations. Galectin-3 predicts all-cause mortality in the general population.

Ultrasound and microbubble-targeted delivery of therapeutic compounds: ICIN Report Project 49: Drug and gene delivery through ultrasound and microbubbles.

The molecular understanding of diseases has been accelerated in recent years, producing many new potential therapeutic targets. A noninvasive delivery system that can target specific anatomical sites would be a great boost for many therapies, particularly those based on manipulation of gene expression. The use of microbubbles controlled by ultrasound as a method for delivery of drugs or genes to specific tissues is promising. It has been shown by our group and others that ultrasound increases cell membrane permeability and enhances uptake of drugs and genes. One of the important mechanisms is that microbubbles act to focus ultrasound energy by lowering the threshold for ultrasound bioeffects. Therefore, clear understanding of the bioeffects and mechanisms underlying the membrane permeability in the presence of microbubbles and ultrasound is of paramount importance. (Neth Heart J 2009;17:82-6.).

[Telomeres and biological ageing in cardiovascular disease]. / Telomeren en biologische veroudering bij hart- en vaatziekten.

The striking variability in the age of onset of and the manifestation/ absence of manifestation of cardiovascular diseases is inadequately explained by conventional risk factors, but may be explained by variation in biological age. Telomere length is possibly a reliable marker of biological age, shorter telomeres reflecting more advanced age. The initial telomere length ofa person is mainly determined by genetic factors. Moreover, the telomere length shortens with each cell division, and exposition to harmful environmental factors also results in shorter telomeres. Leukocytes of patients with atherosclerosis and heart failure display remarkably shorter telomeres compared to leukocytes of healthy subjects of similar age. Conventional cardiovascular risk factors are also associated with telomere length. If telomeres are indeed causally involved in the pathogenesis of cardiovascular disease, this might provide new avenues for future preventive and therapeutic strategies.

[Value of basic and intensive management of patients with heart failure; results of a randomised controlled clinical trial]. / Waarde van lichte en intensieve begeleiding van patiënten met hartfalen; resultaten van het COACH-onderzoek.

OBJECTIVE: To determine the efficacy of 2 nurse-directed programmes of different intensity for the counselling and follow-up of patients hospitalised for heart failure, compared with standard care by a cardiologist. DESIGN: Multicentre randomised clinical trial (www.trialregister.nl: NCT 98675639). METHOD: A total of 1023 patients were randomized after hospitalisation for heart failure to 1 of 3 treatment strategies: standard care provided by a cardiologist, follow-up care from a cardiologist with basic counselling and support by a nurse specialising in heart failure, or follow-up care from a cardiologist with intensive counselling and support by a nurse specialising in heart failure. Primary end points were the time to rehospitalisation due to heart failure or death and the number of days lost to rehospitalisation or death during the 18-month study period. Data were analysed on an intent-to-treat basis. RESULTS: Mean patient age was 71 years, 38% were women, 50% had mild heart failure and 50% had severe heart failure. During the study, 411 patients (40%) were rehospitalised due to heart failure or died from any cause: 42% in the control group, and 41% and 38% in the basic and intensive support groups, respectively (differences not significant). The time to rehospitalisation or death was similar in the 3 groups: hazard ratios for the basic and intensive support groups versus the control group were 0.96 (95% CI: 0.76-1.21; p = 0.73) and 0.93 (95% CI: 0.73-1.17; p = 0.53), respectively. The number of days lost to rehospitalisation or death was 39,960 in the control group; this number was 15% less in the intervention groups, but the difference was not significant. However, there was a trend toward lower mortality in the intervention groups. In all 3 groups, more visits occurred than planned, which may have had a considerable effect on care, notably in the control group. CONCLUSION: The results of this study indicated that the provision of additional counselling and support by a nurse specialising in heart failure as an adjuvant to intensive follow-up care provided by a cardiologist does not always lead to a reduction in rehospitalisation frequency.

Regenerative cell therapy and pharmacotherapeutic intervention in heart failure: Part 1: Cardiovascular progenitor cells, their functions and sources.

It has been postulated that bone marrow derived endothelial progenitor cells (BM-EPCs) are essential for neovascularisation and endothelial repair and are involved in pharmacological treatment, and even its potential targets. There is no doubt that the ultimate success of angiogenic cell therapy will be determined by an appropriate stimulation of certain angiogenic progenitor cell subpopulations. Unfortunately, the biology of EPCs is still poorly understood. In particular, the understanding of endogenous microenvironments within the progenitor cell niches is critical, and will provide us with information about the signalling systems that supply a basis to develop rational pharmacotherapy to enhance the functional activity of endogenous or transplanted progenitor cells. The final success of clinical improvement of progenitor cell-mediated vascular repair and angiogenic therapy depends on a better understanding of EPC biology and a smart therapeutic design. In the first part of this review we first briefly discuss the possible involvement of progenitor cells in chronic heart failure. In part 2 we focus on factors that beneficially affect BMEPCs, with an emphasis on pharmacological molecular pathways involved in BM-EPC-induced neovascularisation. (Neth Heart J 2008;16:305-9.).

Regenerative cell therapy and pharmacotherapeutic intervention in heart failure: Part 2: Pharmacological targets, agents and intervention perspectives.

Regenerative medicine represents a promising perspective on therapeutic angiogenesis in patients with cardiovascular disease, including heart failure. However, previous or ongoing clinical trials show ambiguous outcomes with respect to the benefit of regenerative therapy by means of bone marrow stem cell infusion in myocardial infarction patients. Therefore, it is necessary to set up a rational therapeutic strategy in the treatment of congestive heart failure. Chemokines, cytokines and growth factors, as well as pharmaceutical agents, may have an impact on endothelial progenitor cell (EPC) physiology and thus can provide targets for pharmacological intervention. Indeed, EPCs and stem cell niches both in bone marrow and myocardial tissue can be treated as an integral target for recruitment of EPCs from the bone marrow to the cardiac ischaemic niche. In this article, we individually place the signalling factors in their specified context, and explain their roles in the various phases of neovascularisation (see Part 1). (Neth Heart J 2008;16:337-43.).

Rescue of arterial function by angiotensin-(1-7): towards improvement of endothelial function by drug-eluting stents.

PURPOSE: To explore the hypothesis that stent placement decreases dilator function of various arteries outside the stented segment and that angiotensin- (1-7) improves this function, and to assess the contribution of dilator signal compounds. A further objective was to test the hypothesis that on-stent delivery of Ang-(1-7) reduces neointima formation and improves endothelial function. METHODS: Abdominal aortic stenting or sham operation was performed in the rat four weeks after stenting and treatment with intravenous saline or Ang-(1-7) infusion (24 mug/kg/h); vasomotor function in isolated thoracic aorta and brachial and iliac artery was measured in organ baths. Furthermore, Ang-(1-7)-eluting stents were designed and placed in rat abdominal aorta. Neointima formation and aortic function were tested after four weeks. RESULTS: Relaxation of the thoracic aorta to metacholine was decreased after stenting compared with shams due to a decrease in nitric oxide-mediated response (67% reduction in maximal NO-dependent response). Ang-(1-7) restored the response mainly through increased prostaglandin- and possibly also endothelial-derived hyperpolarising factor-mediated relaxation. Relaxation in the brachial artery decreased after stenting (maximal response dropped by 50%), whilst contractions to phenylephrine increased. Ang-(1-7) normalised vasomotor function. Iliac artery function remained unaltered after stenting but Ang-(1-7) increased maximal relaxations by 65%. Delivery of Ang-(1-7) by means of a drug-eluting stent improved endothelial function. CONCLUSION: Stenting differentially affects dilator and contractile function in various arterial beds. Ang-(1-7) both improves dilator function and normalises contractile function. Delivery of protective peptides such as Ang-(1-7) from the stent is a new therapy option that merits further development and exploration. (Neth Heart J 2008;16:293-8.).

N-terminal pro B-type natriuretic peptide levels predict newly detected atrial fibrillation in a population-based cohort.

BACKGROUND: B-type natriuretic peptide (BNP) is secreted from cardiomyocytes and may reflect haemodynamic abnormalities predisposing to atrial fibrillation (AF). We aimed to investigate whether N-terminal pro BNP (NT-proBNP) is associated with newly detected AF in subjects obtained from the general population. METHODS: From the PREVEND programme (n=8592), we selected all subjects with an available baseline and four-year electrocardiogram and NTproBNP levels at baseline. We excluded subjects with AF at baseline and subjects with a serum creatinine >2.0 mg/dl. RESULTS: In total, 6494 subjects were eligible for the prospective analysis (aged 49+/-12 years, 49.7% men). At four years, AF was detected in 41 (0.6%) subjects. Median NT-proBNP levels at baseline in subjects with newly detected AF after four years was 62.2 (22.6 to 208.5) pg/ml as compared with 35.7 (15.9 to 68.7) pg/ml in those with sinus rhythm (p=0.001). Each 1 standard deviation increment in natural log transformed NT-proBNP was associated with a 54% (5% to 126%, p=0.028) increase in risk for AF after adjustment for other risk factors predisposing to AF. NT-proBNP levels above the sex-specific 80th percentile (97 pg/ml in women and 60 pg/ml in men) were associated with a multivariate odds ratio of 2.65 (1.22 to 5.76, p=0.01) for the occurrence of AF. CONCLUSION: Plasma levels of NT-proBNP predict newly detected AF in subjects obtained from the general population independent of cardiovascular risk factors predisposing to AF. (Neth Heart J 2008;16:73-8.).

Gender-specific correlations of plasminogen activator inhibitor-1 and tissue plasminogen activator levels with cardiovascular disease-related traits.

BACKGROUND: The purpose of this study was to examine the correlations between plasma levels of plasminogen activator inhibitor-1 (PAI-1) and tissue plasminogen activator (t-PA) and cardiovascular disease-related traits in a general population and whether these correlations differed between females and males. METHODS: Plasma PAI-1 and t-PA antigen levels and C-reactive protein (CRP), HDL-cholesterol, triglycerides, total cholesterol, systolic blood pressure, diastolic blood pressure, urinary albumin excretion, and glucose were measured in the population-based PREVEND study in Groningen, the Netherlands (n = 2527). RESULTS: Except for CRP and total cholesterol levels, all traits were significantly different between gender (P < 0.001). PAI-1 levels were correlated with all measured cardiovascular disease-related traits (P < 0.01) in both females and males. Except for urinary albumin excretion, similar results, albeit less significant, were found for t-PA levels. Age-adjusted correlations between PAI-1 and CRP, triglycerides, total cholesterol, systolic blood pressure, and diastolic blood pressure differed significantly between females and males (P < 0.01). Many of the gender differences were predominantly present between premenopausal females and males. CONCLUSION: PAI-1 and t-PA levels were correlated with cardiovascular disease-related traits in subjects obtained from the general population and several of these correlations differed across gender. The correlations found in the present study suggest the presence of coordinated patterns of cardiovascular risk factors and indicate which traits might influence PAI-1 and t-PA levels and thereby provide a framework and potential tool for therapeutic intervention to reduce thromboembolic events in the general population.

Acetylcholine stimulated dilatation and stretch induced myogenic constriction in mesenteric artery of rats with chronic heart failure.

Rats with chronic heart failure (CHF) develop increased myogenic constriction in mesenteric resistance arteries. Here we investigated increased myogenic constriction in relation to alterations in EDHF- and NO-mediated dilatation in CHF-rats. Male Spraque-Dawley rats were subjected to myocardial-infarction or sham-surgery. At 9-10 weeks after surgery, isolated mesenteric artery ring preparations were studied in a wire-myograph. Stretch-induced myogenic constriction was obtained by stepwise increase of the internal circumference diameter (0.5-1.2 L100). Cyclooxygenase- and eNOS-inhibitors were employed to study NO- and EDHF-mediated dilatation in response to acetylcholine. Rats with CHF (n=8), but not sham-rats (n=6), developed significant myogenic constriction. In addition, the contribution of endothelial dilator mediators was significantly altered in CHF-rats, with increased dependency on NO and decreased EDHF-mediated dilatation. Moreover, EDHF-mediated dilatation was inversely correlated with myogenic constriction in individual CHF-rats (r=-0.74, p=0.04). These data demonstrate increased myogenic constriction in mesenteric arteries of rats with CHF post-MI to be correlated to decreased EDHF-mediated dilatation. These findings extend the previous observation that myogenic constriction antagonizes EDHF-mediated dilatation in rat coronary artery under normal conditions, and suggests this relationship also to become functional in mesenteric arteries under pathophysiological conditions of CHF.

Disruption of endothelial caveolae is associated with impairment of both NO- as well as EDHF in acetylcholine-induced relaxation depending on their relative contribution in different vascular beds.

Caveolae represent an important structural element involved in endothelial signal-transduction. The present study was designed to investigate the role of caveolae in endothelium-dependent relaxation of different vascular beds. Caveolae were disrupted by cholesterol depletion with filipin (4x10(-6) g L(-1)) or methyl-beta-cyclodextrin (MCD; 1x10(-3) mol L(-1)) and the effect on endothelium-dependent relaxation was studied in rat aorta, small renal arteries and mesenteric arteries in the absence and presence of L-NMMA. The contribution of NO and EDHF, respectively, to total relaxation in response to acetylcholine (ACh) gradually changed from aorta (71.2+/-6.1% and 28.8+/-6.1%), to renal arteries (48.6+/-6.4% and 51.4+/-6.4%) and to mesenteric arteries (9.1+/-4.0% and 90.9+/-4.1%). Electron microscopy confirmed filipin to decrease the number of endothelial caveolae in all vessels studied. Incubation with filipin inhibited endothelium-dependent relaxation induced by cumulative doses of ACh (3x10(-9)-10(-4) mol L(-1)) in all three vascular beds. In aorta, treatment with either filipin or MCD only inhibited the NO component, whereas in renal artery both NO and EDHF formation were affected. In contrast, in mesenteric arteries, filipin treatment only reduced EDHF formation. Disruption of endothelial caveolae is associated with the impairment of both NO and EDHF in acetylcholine-induced relaxation.

Cardiac overexpression of human VEGF(165) by recombinant Semliki Forest virus leads to adverse effects in pressure-induced heart failure.

Semliki Forest virus (SFV) is an efficient vector for cardiac gene delivery. The relatively short transgene expression induced by SFV seems appropriate for angiogenic gene therapy. We tested the effects of SFV expressing vascular endothelial growth factor (VEGF) on cardiac angiogenesis and heart failure in the mRen2 transgenic rat.Six-week-old mRen2 rats received SFV-VEGF or control virus (n=7 each) administered intracoronarily. Twelve days after transfection, cardiac capillary density and function were assessed. Capillary density in cardiac regions where SFV expression was highest had decreased by 20% in the SFV-VEGF-treated group. The decrease in capillary density was accompanied by impaired systolic function as illustrated by increased endsystolic volumes and a 34% decrease in cardiac output.We conclude that the time frame of SFV expression is sufficient to induce structural alterations, but that VEGF in mRen2 transgenic rats did not elicit the expected angiogenic effect. Rather, capillary density was decreased and subsequently cardiac function was impaired. This paradoxical finding is possibly related to the pathophysiology associated with this model and warrants caution if one is to pursue VEGF-mediated, angiogenic therapy before proceeding to a clinical setting. (Neth Heart J 2007;15:335-41.).

Clinical characteristics, cardiac events and coronary angiographic findings in the prospective PREVEND cohort: an observational study.

BACKGROUND: The use of invasive procedures has mostly been studied in retrospective (multi)- national registries. Limited evidence exists on the association between microalbuminuria and coronary artery disease (CAD). METHODS: The incidence of major adverse cardiac events (MACE) and invasive cardiac procedures was registered between 1997 and 2003 in 8139 subjects, without prior documented CAD, in the PREVEND cohort study (the Netherlands), in which the focus is on microalbuminuria and cardiovascular risk. Qualitative coronary angiographic analysis was performed. RESULTS: During 5.5 years of follow-up, a first MACE occurred in 271 (3.3%) and a first coronary angiography (CAG) was performed in 264 (3.2%) subjects. Of these, 216 CAGs were available for qualitative angiographic analysis. Indications for CAG were stable angina in 129, acute coronary syndrome (ACS) in 55 and ST-elevation myocardial infarction (STEMI) in 32 subjects. Obstructive coronary artery disease was present in 61, 53 and 30 subjects, respectively. A revascularisation was performed in 50 (39%), 50 (91%) and 25 (78%) subjects, respectively. Microalbuminuria was associated with a first MACE, after adjustment for established risk factors. Microalbuminuria was present at baseline in 9% of subjects with normal coronary arteries, in 21% of subjects with one- and two-vessel CAD and in 39% of subjects with threevessel or left main CAD at CAG during follow-up (Ptrend=0.005). CONCLUSION: This large cohort study shows that two-thirds of diagnostic CAGs for stable angina were not followed by a revascularisation, in contrast to CAGs for STEMI or ACS. Furthermore, this study shows that microalbuminuria is associated with CAD. (Neth Heart J 2007;15:133-41.).

Determinants of increased angiotensin II levels in severe chronic heart failure patients despite ACE inhibition.

INTRODUCTION: The beneficial effects of ACE inhibitors are generally ascribed to blockade of neurohormonal activation. However, especially in chronic heart failure (CHF) patients plasma angiotensin II and aldosterone levels can be elevated despite ACE inhibition, the so-called ACE escape. In the present study, we aimed to identify the frequency and determinants of ACE escape in CHF patients. METHODS: We studied 99 stable chronic heart failure patients (NYHA class III and IV, 66% ischemic etiology) receiving long-term therapy with ACE inhibitors. In all patients, cardiac, renal, and neurohormonal parameters were measured. ACE escape was defined as plasma angiotensin level > or = 16 pmol/L. RESULTS: Mean (+/- SD) left ventricular ejection fraction of our 99 patients (79 men and 20 women, age 69 +/- 12 years) was 28 +/- 10%. In addition to an ACE inhibitor, 93% of patients received diuretics, 71% a beta-blocker, and 49% spironolactone. None of the patients used an angiotensin receptor blocker. In our population, 45% of the patients had an angiotensin II plasma concentration higher than 16 pmol/L (median concentration was 14.1 pmol/L). Spironolactone use was an independent predictor of elevated plasma angiotensin II levels. Furthermore, spironolactone users had significantly higher plasma active renin protein and aldosterone levels. Plasma angiotensin II concentration was positively correlated to active renin, plasma angiotensin I and plasma aldosterone. No correlation was found between plasma angiotensin II levels and serum ACE activity, dose of ACE inhibitor, or duration of use. CONCLUSION: In a group of severe chronic heart failure patients, 45% had elevated plasma angiotensin II levels independent of serum ACE activity despite long-term ACE inhibitor use. Although a causal link could not be proven, an association was found between spironolactone use and active renin protein, angiotensin II and aldosterone levels, suggesting that escape from ACE is mainly caused by a feedback mechanism.

Deletion-type allele of the angiotensin-converting enzyme gene is associated with progressive ventricular dilation after anterior myocardial infarction. Captopril and Thrombolysis Study Investigators.

OBJECTIVES: This study sought to determine whether patients who are homozygous for the deletion (D)-type allele of the angiotensin-converting enzyme gene display augmented ventricular dilation after myocardial infarction. BACKGROUND: Recent evidence suggests that the deletion-type allele of the angiotensin-converting enzyme gene (DD genotype) is associated with an increased prevalence of myocardial infarction and myocardial hypertrophy. However, it is unknown whether the DD genotype is associated with adverse cardiac remodeling. To address this question we determined the genotype in patients enrolled in the Captopril and Thrombolysis Study (CATS), a prospective trial in which patients received either captopril or placebo during and after thrombolysis for a first anterior myocardial infarction. METHODS: Cardiac volume was determined by echocardiography immediately after thrombolysis and at 1-year follow-up. The genotype for the angiotensin-converting enzyme was determined in 96 patients. Norepinephrine levels were assessed during and immediately after thrombolysis. RESULTS: Immediately after thrombolysis, cardiac volume did not differ between genotype groups. However, at 1-year follow-up, both end-systolic and end-diastolic left ventricular volumes were significantly greater in the DD-genotype group. Norepinephrine increased to higher levels in the DD-genotype group that received placebo therapy. Captopril treatment effectively blunted both the norepinephrine increase and cardiac dilation in the DD-genotype group. CONCLUSIONS: This exploratory study suggests that homozygosity for the angiotensin-converting enzyme deletion-type allele is associated with augmented neurohumoral activation as well as augmented cardiac dilation after an acute anterior myocardial infarction, an effect that may be susceptible to angiotensin-converting enzyme inhibition.

Which patient benefits from early angiotensin-converting enzyme inhibition after myocardial infarction? Results of one-year serial echocardiographic follow-up from the Captopril and Thrombolysis Study (CATS).

OBJECTIVES: In this study we sought to investigate the effect of intervention with captopril within 6 h of the onset of myocardial infarction on left ventricular volume and clinical symptoms of heart failure in relation to infarct size during a 1-year follow-up period. BACKGROUND: Remodeling of the heart starts in the early phase of myocardial infarction and is associated with an adverse prognosis. Angiotensin-converting enzyme inhibition started in the subacute or late phase after myocardial infarction has been shown to improve prognosis. METHODS: In the Captopril and Thrombolysis Study, 298 patients with a first anterior myocardial infarction treated with intravenous streptokinase were randomized to receive either oral captopril (25 mg three times a day) or placebo. The left ventricular volume index was assessed by two-dimensional echocardiography within 24 h, on days 3, 10 and 90 and after 1 year. RESULTS: A small but significant increase in left ventricular volume indexes was observed after 12 months. Using a random coefficient model, no significant treatment effect on left ventricular volumes could be detected. In contrast, when survival models were used, the occurrence of left ventricular dilation was significatnly lower in captopril-treated patients (p = 0.018). In addition, the incidence of heart failure was lower in the captopril group (p < 0.03). This effect appeared early and was most obvious in patients with a medium-sized infarct (p = 0.04) and was not present in large infarcts. CONCLUSIONS: Very early treatment with captopril after myocardial infarction significantly reduces the occurrence of early dilation and the progression to heart failure. These data underscore the importance of early treatment. Furthermore, patients with intermediate infarct size benefit the most from this treatment strategy.