Hans-Werner Hense

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.

Framingham risk function overestimates risk of coronary heart disease in men and women from Germany—results from the MONICA Augsburg and the PROCAM cohorts

BACKGROUND The prediction of the absolute risk of coronary heart disease (CHD) is commonly based on risk prediction equations that originate from the Framingham Heart Study. However, differences in population risk levels compromise the external validity of these risk functions. SETTING AND STUDY POPULATION Participants aged 35-64 years from the MONICA Augsburg (2861 men and 2925 women) and the PROCAM (5527 men and 3155 women) cohorts were followed-up with regard to incident non-fatal myocardial infarction (MI) and fatal coronary events. For each participant, the predicted absolute risk of fatal plus non-fatal events was derived using Framingham risk equations. Predicted and actually observed risks were compared. RESULTS The two cohorts were similar in their baseline characteristics. Coronary risk predicted by the Framingham risk function substantially exceeded the risk actually observed in the German cohorts, irrespective of gender. The difference between predicted and observed absolute CHD risk increased with age while the ratio of predicted over observed risk remained constant at about a value of 2. Taking potentials for underascertainment in the German cohorts due to unrecognised MI and sudden deaths into account, the residual magnitude of risk overestimation by the Framingham risk function is probably at least 50%. CONCLUSIONS Local guidelines for the management of patients with risk factors need to correct for this overestimation to avoid inadequate initiation of treatment and inflation of costs in primary prevention. Similar studies should be conducted in other populations with the aim of defining appropriate factors that calibrate absolute risk predictions to local population levels of CHD risk.

Effects of Estrogen Replacement Therapy on the Renin-Angiotensin System in Postmenopausal Women

BACKGROUND Oral estrogen replacement therapy (ERT) is known to stimulate the synthesis of angiotensinogen. The effects of such therapy on renin, ACE, and aldosterone are less clear. This seems noteworthy, however, since further activation of the system could be disadvantageous to postmenopausal women who replace estrogen in the context of heart failure, coronary artery disease, or hypertension. METHODS AND RESULTS Estrogen status and components of the renin-angiotensin system were examined in a population-based sample of postmenopausal women and age-matched men. Renin was quantified immunoradiometrically, ie, independent of substrate abundance; aldosterone, angiotensinogen, and ACE activity were determined by standard methods. Renin levels were lower in women with ERT (n = 107; 12.0 +/- 0.7 mU/L) compared with women without ERT (n = 223; 16.6 +/- 0.9 mU/L; P = .001) or men (n = 342, 20.5 +/- 1.5 mU/L, P < .0001). In contrast, angiotensinogen was higher in women with ERT (1.36 +/- 0.08 mg/L) compared with women without ERT (1.03 +/- 0.02 mg/L; P < .0001) or compared with men (0.97 +/- 0.01 mg/L; P < .0001). Renin suppression was seen with either oral or transdermal estrogen replacement (-30% and -31%, respectively; both P < .001). In contrast, the increase of angiotensinogen was limited to women taking oral estrogens (+58%, P < .001). Multivariate analysis revealed that these estrogen effects were independent of age, body mass index, blood pressure, and/or antihypertensive medication. Finally, only marginal differences between groups were observed for serum ACE activity and aldosterone. CONCLUSIONS Aside from a well-documented induction of angiotensinogen, ERT is related to a substantial suppression of renin, a phenomenon that might have received little attention because of widely used indirect measurements of the hormone.

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.

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.

Association of serum uric acid with all-cause and cardiovascular disease mortality and incident myocardial infarction in the MONICA Augsburg cohort. World Health Organization Monitoring Trends and Determinants in Cardiovascular Diseases.

Because previous findings have been inconsistent, we explored the association of serum concentrations of uric acid with all-cause and cardiovascular disease mortality and myocardial infarction prospectively. We used data from 1,044 men who are members of the World Health Organization Monitoring Trends and Determinants in Cardiovascular Diseases (MONICA) Augsburg cohort. The men, 45-64 years of age in 1984-1985, were followed through 1992. There were 90 deaths, 44 of which were related to cardiovascular disease; 60 men developed incident nonfatal or fatal myocardial infarction. We estimated hazard rate ratios from Cox proportional hazard models. Uric acid levels > or =373 micromol/liter (fourth quartile) vs < or =319 micromol/liter (first and second quartile) independently predicted all-cause mortality [hazard rate ratio = 2.8; 95% confidence interval (CI) = 1.6-5.0] after adjustment for alcohol, total cholesterol/high-density lipoprotein cholesterol ratio, hypertension, use of diuretic drugs, smoking, body mass index, and education. The adjusted risk of cardiovascular disease mortality was 2.2 (95% CI = 1.0-4.8), and that of myocardial infarction was 1.7 (95% CI = 0.8-3.3). Although residual confounding cannot be excluded, our results are among the few, in men, demonstrating a strong positive association of elevated serum uric acid with all-cause mortality. Future investigations may be able to evaluate whether uric acid contributes independently to the development of cardiovascular disease or is simply a component of the atherogenic metabolic condition known as the insulin resistance syndrome.

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.

Evaluation of brain natriuretic peptide as marker of left ventricular dysfunction and hypertrophy in the population

Objective To evaluate brain natriuretic peptide (BNP) as marker of left ventricular (LV) dysfunction and hypertrophy in a population-based sample of 610 middle-aged subjects (50–67 years) who were further characterized with respect to hemodynamic and anthropometric parameters and by echocardiography. Results Left ventricular (LV) systolic function, LV mass-index, age, gender, heart rate, and medication with beta adrenergic receptor blockers were significant and independently correlated with BNP (multivariate analysis, P < 0.05 each). As compared to subjects with normal LV function and mass-index (control), subjects with LV dysfunction (LV fractional shortening < 28%) or hypertrophy (LV mass-index > 110 g/m2 in women and > 134 g/m2 in men) were characterized by increased BNP. The increase in BNP associated with LV hypertrophy (n = 69, +101% versus control, P < 0.0001) was similar in magnitude to that associated with LV dysfunction (n = 39, +98% versus control, P < 0.03). These increases were markedly exceeded in subjects with severe LV dysfunction (n = 11, LV fractional shortening < 22%, BNP +197% versus control, P < 0.01), particularly in the presence of concomitant hypertrophy (n = 7, +227%, P < 0.01). The predictive values of BNP varied considerably with the degree of LV dysfunction and the presence or absence of concomitant LV hypertrophy. With 0.81, the highest area under the receiver operator characteristic curve was obtained for the detection of severe LV dysfunction and concomitant hypertrophy and sensitivity, specificity, positive and negative predictive value for this condition were 71, 86, 7 and 99.5%, respectively, for a cut-off of 34 pg/ml. Conclusions The current study provides new insight into regulation and diagnostic value of BNP in middle-aged subjects and demonstrates important independent effects of LV function and mass upon BNP plasma concentrations. Although measurement of BNP cannot be recommended for the detection of marginally impaired LV function in the population, it may be helpful to suggest or exclude severe LV dysfunction with concomitant hypertrophy.

Regional disparities of hypertension prevalence and management within Germany.

Objective To investigate regional variations in the prevalence and management of hypertension in two communities in the north-east and the south-west of Germany. Study setting Two population-based surveys of men and women aged 25–74 years, using a common standardized protocol: the Study of Health in Pomerania (SHIP; 3744 participants) and the Kooperative Gesundheitsforschung in der Region Augsburg (KORA; 4224 participants). Main outcome measures Comparison of SHIP and KORA with regard to mean systolic (SBP) and diastolic blood pressure (DBP), prevalence of hypertension, percentage of awareness, treatment and control of hypertension in the community, by age and sex. Results The overall age-standardized prevalence of hypertension for men was 60.1% in SHIP and 41.4% in KORA; the corresponding values for women were 38.5 and 28.6%. Mean blood pressure differences were present in each 10-year age group and sex. The overall SBP difference between SHIP and KORA was 8.2 mmHg (95% confidence interval 7.2–9.3) in men and 6.3 mmHg (5.3–7.3) in women, the respective DBP differences were 3.8 mmHg (3.2–4.5) and 3.6 mmHg (3.0–4.2). Nevertheless, the percentage of awareness, treatment and control of hypertension was strikingly similar in the two studies (women, P = 0.858; and men, P = 0.564). Conclusions The entire distribution of diastolic and systolic blood pressure values was shifted upwards in the north-eastern as compared to the south-western German population samples and the prevalences of hypertension differed accordingly. Despite such substantial epidemiologic differences, the community management of hypertension was of almost identical quality.

The associations of body size and body composition with left ventricular mass: impacts for indexation in adults ☆

OBJECTIVES We investigated the relationship between body size, body composition and left ventricular mass (LVM) in adults, and assessed the impact of different indexations of LVM on its associations with gender, adiposity and blood pressure. BACKGROUND The best way to normalize LVM for body size to appropriately distinguish physiologic adaptation from morbid heart morphology was discussed. METHODS We undertook a community survey of 653 men and 718 women, aged 25 to 74 years. Lean body mass (LBM) was determined by bioelectric impedance analyses and LVM was assessed by two-dimensional guided M-mode echocardiography. RESULTS After traditional indexations to body height, body height2.7, or body surface area, men had higher LVM than women (p < 0.001). These gender differences disappeared (p > 0.05) when LVM was indexed to LBM. The type of indexation also modified the strength of the association between adiposity and LVM. The estimated impact of body fat on LVM indexed to LBM was less than half that obtained with traditional indexations. In contrast, the magnitude of the associations of blood pressure with LVM was entirely independent of the type of indexation. CONCLUSIONS This study showed the prominent influence of body composition on adult heart size. Indexation for LBM removed gender differences for LVM and reduced the impact of adiposity, but left the effects of blood pressure unchanged. We suggest that this approach be used for clinical and research applications.