Günter A.J. Riegger

Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: randomised trial—the Losartan Heart Failure Survival Study ELITE II

BACKGROUND The ELITE study showed an association between the angiotensin II antagonist losartan and an unexpected survival benefit in elderly heart-failure patients, compared with captopril, an angiotensin-converting-enzyme (ACE) inhibitor. We did the ELITE II Losartan Heart Failure Survival Study to confirm whether losartan is superior to captopril in improving survival and is better tolerated. METHODS We undertook a double-blind, randomised, controlled trial of 3,152 patients aged 60 years or older with New York Heart Association class II-IV heart failure and ejection fraction of 40% or less. Patients, stratified for beta-blocker use, were randomly assigned losartan (n=1,578) titrated to 50 mg once daily or captopril (n=1,574) titrated to 50 mg three times daily. The primary and secondary endpoints were all-cause mortality, and sudden death or resuscitated arrest. We assessed safety and tolerability. Analysis was by intention to treat. FINDINGS Median follow-up was 555 days. There were no significant differences in all-cause mortality (11.7 vs 10.4% average annual mortality rate) or sudden death or resuscitated arrests (9.0 vs 7.3%) between the two treatment groups (hazard ratios 1.13 [95.7% CI 0.95-1.35], p=0.16 and 1.25 [95% CI 0.98-1.60], p=0.08). Significantly fewer patients in the losartan group (excluding those who died) discontinued study treatment because of adverse effects (9.7 vs 14.7%, p<0.001), including cough (0.3 vs 2.7%).

Association between a Deletion Polymorphism of the Angiotensin-Converting-Enzyme Gene and Left Ventricular Hypertrophy

BACKGROUND Epidemiologic studies have shown that left ventricular hypertrophy is often found in the absence of an elevated cardiac workload. To investigate whether such hypertrophy is determined in part by genetic factors, we studied the association between this condition, as assessed by electrocardiographic criteria, and a deletion (D)-insertion (I) polymorphism of the angiotensin-converting-enzyme (ACE) gene. METHODS A population-based random sample of 711 women and 717 men 45 to 59 years of age was studied cross-sectionally in Augsburg, Germany. Electrocardiographic indexes, including the Sokolow-Lyon index, Minnesota Code 3.1, and the Rautaharju equations, were used to detect left ventricular hypertrophy. The status of the ACE gene with respect to the deletion-insertion allele was determined by the polymerase chain reaction in all subjects with left ventricular hypertrophy and an identical number of control subjects without the condition who were matched for age, sex, and blood-pressure status. RESULTS We identified 141 women and 149 men with evidence of left ventricular hypertrophy. Among these subjects, an excess were homozygous for the D allele of the ACE gene (odds ratio, 1.76; 95 percent confidence interval, 1.22 to 2.53; P = 0.003). The association of the DD genotype with left ventricular hypertrophy was stronger in men (odds ratio, 2.63; 95 percent confidence interval, 1.50 to 4.64; P < 0.001) than in women and was most prominent when blood-pressure measurements were normal (odds ratio, 4.05; 95 percent confidence interval, 1.76 to 9.28; P = 0.001). This association was evident for each of the scores recorded in the electrocardiographic testing for left ventricular hypertrophy. CONCLUSIONS The findings suggest that left ventricular hypertrophy is partially determined by genetic disposition. They identify the DD genotype of ACE as a potential genetic marker associated with an elevated risk of left ventricular hypertrophy in middle-aged men.

Effects of high-dose versus low-dose losartan on clinical outcomes in patients with heart failure (HEAAL study): a randomised, double-blind trial.

BACKGROUND Angiotensin-receptor blockers (ARBs) are effective treatments for patients with heart failure, but the relation between dose and clinical outcomes has not been explored. We compared the effects of high-dose versus low-dose losartan on clinical outcomes in patients with heart failure. METHODS This double-blind trial was undertaken in 255 sites in 30 countries. 3846 patients with heart failure of New York Heart Association class II-IV, left-ventricular ejection fraction 40% or less, and intolerance to angiotensin-converting-enzyme (ACE) inhibitors were randomly assigned to losartan 150 mg (n=1927) or 50 mg daily (n=1919). Allocation was by block randomisation stratified by centre and presence or absence of beta-blocker therapy, and all patients and investigators were masked to assignment. The primary endpoint was death or admission for heart failure. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00090259. FINDINGS Six patients in each group were excluded because of poor data quality. With 4.7-year median follow-up in each group (IQR 3.7-5.5 for losartan 150 mg; 3.4-5.5 for losartan 50 mg), 828 (43%) patients in the 150 mg group versus 889 (46%) in the 50 mg group died or were admitted for heart failure (hazard ratio [HR] 0.90, 95% CI 0.82-0.99; p=0.027). For the two primary endpoint components, 635 patients in the 150 mg group versus 665 in the 50 mg group died (HR 0.94, 95% CI 0.84-1.04; p=0.24), and 450 versus 503 patients were admitted for heart failure (0.87, 0.76-0.98; p=0.025). Renal impairment (n=454 vs 317), hypotension (203 vs 145), and hyperkalaemia (195 vs 131) were more common in the 150 mg group than in the 50 mg group, but these adverse events did not lead to significantly more treatment discontinuations in the 150 mg group. INTERPRETATION Losartan 150 mg daily reduced the rate of death or admission for heart failure in patients with heart failure, reduced left-ventricular ejection fraction, and intolerance to ACE inhibitors compared with losartan 50 mg daily. These findings show the value of up-titrating ARB doses to confer clinical benefit. FUNDING Merck (USA).

Prevalence of left ventricular diastolic dysfunction in the community. Results from a Doppler echocardiographic-based survey of a population sample.

AIMS The prevalence of left ventricular diastolic abnormalities in the general population is largely unclear. Thus, the aim of this study was, firstly, to identify abnormal diastolic function by echocardiography in an age-stratified population-based European sample (MONICA Augsburg, n=1274, 25 to 75 years, mean 51+/-14) and, secondly, to analyse clinical and anthropometric parameters associated with diastolic abnormalities. METHODS AND RESULTS The overall prevalence of diastolic abnormalities, as defined by the European Study Group on Diastolic Heart Failure (i.e. age dependent isovolumic relaxation time (92-105 ms) and early (E-wave) and late (A-wave) left ventricular filling (E/A-ratio, 1-0.5)) was 11.1%. When only subjects treated with diuretics or with left atrial enlargement were considered (suggesting diastolic dysfunction) the prevalence was 3.1%. The prevalence of diastolic abnormalities varied according to age: from 2.8% in individuals aged 25-35 years to 15.8% among those older than 65 years (P<0.01). Significantly higher rates of diastolic abnormalities were observed in men as compared to women (13.8% vs 8.6%, P<0.01). Independent predictors of diastolic abnormalities were arterial hypertension, evidence of left ventricular (LV) hypertrophy, and coronary artery disease. Interestingly, in the absence of these predisposing conditions, diastolic abnormalities (4.3%) or diastolic dysfunction (1.1%) were rare, even in subjects older than 50 years of age (4.6%) and (1.2%), respectively. In addition to these factors, diastolic dysfunction was related to high body mass index, high body fat mass, and diabetes mellitus. CONCLUSION The prevalences of diastolic abnormalities and diastolic dysfunction are higher than that of systolic dysfunction and are increased (despite age-dependent diagnostic criteria) in the elderly. However, in the absence of risk factors for diastolic abnormalities or diastolic dysfunction, namely LV hypertrophy, arterial hypertension, coronary artery disease, obesity and diabetes the condition is rare even in elderly subjects. These data allow speculation on whether diastolic heart failure may be prevented by improved implementation of measures directed against predisposing conditions.

A comprehensive linkage analysis for myocardial infarction and its related risk factors

Coronary artery disease and myocardial infarction (MI) are leading causes of death in the western world. Numerous studies have shown that risk factors such as diabetes mellitus, arterial hypertension and hypercholesterolemia contribute to the development of the disease. Although each risk factor by itself is partly under genetic control, a positive family history is an independent predictor, which suggests that there are additional susceptibility genes. We have scanned the whole genome in 513 families to identify chromosomal regions linked to myocardial infarction and related risk factors that are known to be under genetic control. Here we show, by using variance component analysis and incorporating risk factors, that risk of myocardial infarction maps to a single region on chromosome 14 with a significant lod score of 3.9 (pointwise P=0.00015, genome-wide P<0.05), providing evidence of a principal MI locus. To characterize this locus we analyzed each risk factor by itself. Serum concentrations of lipoprotein (a) show linkage to both the apolipoprotein (a) locus (lod score 26.99) and a new locus on chromosome 1 (lod score 3.8). There is suggestive linkage for diabetes mellitus on chromosome 6 (lod score 2.96), for hypertension on chromosomes 1 and 6, for high-density and low-density lipoprotein cholesterol on chromosomes 1 and 17, and for triglyceride concentrations on chromosome 9. Although some of these risk factors overlap with previously identified loci, none overlaps with the newly identified susceptibility locus for myocardial infarction and coronary artery disease.

Association of Early Repolarization Pattern on ECG with Risk of Cardiac and All-Cause Mortality: A Population-Based Prospective Cohort Study (MONICA/KORA)

In a population-based cohort study of middle-aged people in Central Europe, Stefan Kääb and colleagues find an association between electrocardiographic early repolarization pattern and mortality risk.

Association Between a Polymorphism in the G Protein β3 Subunit Gene and Lower Renin and Elevated Diastolic Blood Pressure Levels

Gi proteins mediate the intracellular effects of many vasoactive and proliferative stimuli. Recently such signaling was found to be enhanced in cultured cells of some hypertensive subjects. A polymorphism at position 825 (C-->T) of the G protein beta3 subunit gene (GNB3) was strictly related to this phenotype. The aim of the present investigation was to test the association between this polymorphism and blood pressure and plasma renin levels in humans. A population-based sample (n=608) was analyzed by questionnaire and characterized for blood pressure; plasma renin, prorenin, and aldosterone levels; and Gbeta3 C825T allele status. In individuals without antihypertensive medication (n=474; age range, 52 to 67 years), the polymorphism was mildly associated with diastolic blood pressure (CC: 88.6+/-0.3 mm Hg, n=218; versus CT: 90.1+/-0.7 mm Hg, n=209; versus TT: 91.8+/-1.7 mm Hg, n=47; P=0.02 for trend) but not with systolic blood pressure. Furthermore, the 825T allele was also significantly associated with lower renin and prorenin levels, whereas the aldosterone to renin ratio was elevated in these subjects. Significant associations between the 825T allele and diastolic blood pressure, plasma renin, and prorenin levels (inverse), and the aldosterone to renin ratio persisted after adjustment for age, gender, body mass index, and systolic blood pressure. Finally, when the entire sample was considered and an adjustment was made for covariates, the presence of arterial hypertension and the use of antihypertensive medication were both 1. 8-fold higher in the TT than in the CC genotype group (P<0.05 and P=0.06, respectively). This observation, if replicated in further studies, suggests a molecular mechanism that unifies a higher diastolic blood pressure, a lower renin level, and an elevated aldosterone to renin ratio, ie, a combination of features frequently found in patients with arterial hypertension.

Determinants of interindividual variation of renin and prorenin concentrations: evidence for a sexual dimorphism of (pro)renin levels in humans

Background Plasma renin concentrations are an important factor in cardiovascular risk profiling. Objective To investigate the effects of sex, medication, and anthropometric factors that may contribute to the interindividual variation in the plasma concentrations of renin and its precursor prorenin. Design and methods Prorenin and renin levels in 327 men and 383 women, aged 52–69 years, who participated in a 1994 reexamination of a previous population survey in Bavaria, were measured by immunoradiometric assay. Results Prorenin and renin levels in men were significantly higher than those in women, those in women without estrogen replacement therapy were significantly higher than those in women with estrogen replacement therapy, and those in diabetics were significantly higher than those in nondiabetics. Prorenin level was correlated negatively to blood pressure and positively to age and the use of diuretics; it was normal in subjects using angiotensin converting enzyme inhibitors and β-adrenergic antagonists (β-blockers). Renin level was correlated negatively to atrial natriuretic peptide level and the use of b-blockers, and it was elevated above normal levels in subjects using angiotensin converting enzyme inhibitors and diuretics as well as in subjects who had previously suffered myocardial infarction. After exclusion of data for women being administered estrogen replacement therapy, multivariate analysis revealed that sex (P < 0.001), age (P < 0.02), blood pressure (P < 0.002), diabetes (P < 0.05), and the use of angiotensin converting enzyme inhibitors (P < 0.002), β-blockers (P < 0.001), and diuretics (P < 0.05) were independent determinants of plasma prorenin. Plasma renin was independently related to atrial natriuretic peptide level (P < 0.01) and the use of angiotensin converting enzyme inhibitors (P < 0.001), b-blockers (P < 0.001), and diuretics (P < 0.05). Conclusions These data demonstrate that there is a sexual dimorphism of prorenin levels in humans, suggesting that sex hormones affect the regulation of the renin gene. Data confirm previous reports of elevated prorenin levels in diabetics and older subjects, as well as of lower than normal prorenin levels in subjects with hypertension in smaller populations. Our findings may help to clarify the potential (patho)physiologic functions of prorenin and to identify the factors that influence the constitutive secretion and intracellular processing of this prohormone.

Development of heart failure following isoproterenol administration in the rat: role of the renin–angiotensin system

OBJECTIVE High dosages of catecholamines induce cardiomyocyte necrosis and interstitial fibrosis in rats. We investigated whether this initial damage is followed by the development of heart failure and assessed the particular role of the renin-angiotensin system using ramipril. METHODS AND RESULTS Following the administration of 0 mg or 150 mg isoproterenol/kg 6 groups of Wistar rats were followed for 2 or 16 weeks: Sham, isoproterenol, isoproterenol + ramipril. Isoproterenol induced significant increases of echocardiographically measured left ventricular end-diastolic posterior wall thickness and dimension, whereas ramipril treatment significantly attenuated these changes. Left ventricular end-diastolic pressure was markedly increased in isoproterenol-treated rats and normalized following ramipril. Isoproterenol rats were further characterized by hormonal activations including transient elevations of plasma renin activity, aldosterone and cardiac angiotensin converting enzyme activity. Histomorphological characterization of isoproterenol-treated hearts demonstrated cardiomyocyte necrosis and reparative fibrosis. Ramipril treatment only slightly reduced the amount of necrosis as well as the expression of extracellular matrix proteins. CONCLUSIONS In rats, a toxic dosage of isoproterenol caused characteristic myocardial damage that subsequently resulted in mild heart failure. Ramipril administration following isoproterenol was highly effective to attenuate hemodynamic and hormonal alterations as well as the development of left ventricular hypertrophy, but had only little influence on the expression of extracellular matrix proteins. Since angiotensin converting enzyme inhibition had no impact on the initial myocardial injury, the development of heart failure in this model seems to require functional integrity of the renin-angiotensin system.

Effect of Compensated Renal Dysfunction on Approved Heart Failure Markers Direct Comparison of Brain Natriuretic Peptide (BNP) and N-Terminal Pro-BNP

Brain natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP) are markers of heart failure. Although renal dysfunction may increase plasma concentrations, the magnitude of this effect has not been assessed in a head-to-head comparison between the clinically approved tests. We assessed the effect of compensated renal dysfunction on BNP (Triage BNP; Biosite) and NT-proBNP (elecsys proBNP; Roche) in 469 randomly selected stable outpatients after myocardial infarction (MI; Monitoring Trends and Determinants in Cardiovascular Diseases [MONICA] register Augsburg) who were characterized with respect to renal function (glomerular filtration rate [GFR]; Cockroft method) and left ventricular (LV) ejection fraction (EF) and mass (2D echocardiography). BNP and NT-proBNP were elevated in MI patients with LV dysfunction (LVD; EF <35%) compared with MI patients with preserved EF (>45%; BNP 139±27 pg/mL versus 75±6; NT-proBNP 816±237 pg/mL versus 243±20; both P<0.03). Among all MI patients, the prevalence of renal dysfunction (GFR <85 mL/min) was 24%. BNP and NT-proBNP were significantly elevated in MI patients with renal dysfunction (BNP 132±17 pg/mL versus 68±4 without renal dysfunction; NT-proBNP 535±80 pg/mL versus 232±19; both P<0.05), and both markers were correlated with GFR in univariate and multivariate analyses (all P<0.01). When binary cut-off values were stratified according to the absence or presence of renal dysfunction (BNP 75 pg/mL and 125 pg/mL, respectively; NT-proBNP 100 pg/mL and 350pg/mL, respectively), the predictive power of both markers for the detection of LVD increased substantially. BNP and NT-proBNP are almost similarly influenced by mild-to-moderate renal dysfunction. Renal dysfunction is a potential cause of elevated marker concentrations in the absence of LVD, and cut-off concentrations should be stratified according to renal function.