Exploiting Distributed, Heterogeneous and Sensitive Data Stocks while Maintaining the Owner's Data Sovereignty.

BACKGROUND: To achieve statistical significance in medical research, biological or data samples from several bio- or databanks often need to be complemented by those of other institutions. For that purpose, IT-based search services have been established to locate datasets matching a given set of criteria in databases distributed across several institutions. However, previous approaches require data owners to disclose information about their samples, raising a barrier for their participation in the network. OBJECTIVE: To devise a method to search distributed databases for datasets matching a given set of criteria while fully maintaining their owner's data sovereignty. METHODS: As a modification to traditional federated search services, we propose the decentral search, which allows the data owner a high degree of control. Relevant data are loaded into local bridgeheads, each under their owner's sovereignty. Researchers can formulate criteria sets along with a project proposal using a central search broker, which then notifies the bridgeheads. The criteria are, however, treated as an inquiry rather than a query: Instead of responding with results, bridgeheads notify their owner and wait for his/her decision regarding whether and what to answer based on the criteria set, the matching datasets and the specific project proposal. Without the owner's explicit consent, no data leaves his/her institution. RESULTS: The decentral search has been deployed in one of the six German Centers for Health Research, comprised of eleven university hospitals. In the process, compliance with German data protection regulations has been confirmed. The decentral search also marks the centerpiece of an open source registry software toolbox aiming to build a national registry of rare diseases in Germany. CONCLUSIONS: While the sacrifice of real-time answers impairs some use-cases, it leads to several beneficial side effects: improved data protection due to data parsimony, tolerance for incomplete data schema mappings and flexibility with regard to patient consent. Most importantly, as no datasets ever leave their institution, owners can reject projects without facing potential peer pressure. By its lower barrier for participation, a decentral search service is likely to attract a larger number of partners and to bring a researcher into contact with the right potential partners.

[Distribution, determinants and reference values of left ventricular parameters in the general population--results of the MONICA/KORA echocardiography studies]. / Verteilung, Determinanten und Referenzwerte linksventrikulärer Parameter in der Allgemeinbevölkerung -- Resultate der MONICA/KORA-Echokardiographiestudien.

For successful fighting against the burden of cardiovascular disease in the community a comprehensive knowledge about the prevalence and the impact of underlying risk factors is important. The present paper summarises some studies undertaken on more than 2000 persons from the MONICA/KORA-studies (parts of S1 and S3) where left ventricular mass (LVM) and other left ventricular parameters were determined by echocardiography. We especially investigated the associations of LVM with blood pressure and obesity. A special focus was on sex-specific factors in the determination of LVM and the influence of different indices of body size when normalising LVM. It could be shown that hypertension and obesity are major determinants of LV hypertrophy. Especially women with both hypertension and obesity on showed a high prevalence of concentric hypertrophy, significantly more than men. We also showed that the prevalence of LV hypertrophy in a representative sample of the general population (25 to 74 years) is 17.5 % for men, and 18.5 % for women. This underscores the need for primary and secondary prevention regarding the development of LV hypertrophy. Finally, our data in a selected group of normal subjects (reference sample) may be used for the development of reference values for left ventricular parameters in the general German population.

Cardiovascular phenotypes and functional parameters in the general population--results of the MONICA/KORA studies.

The MONICA/KORA surveys are characterized by a careful and broad investigation of multiple cardiovascular phenotypes. Particularly, repeated blinded measurements of blood pressure, comprehensive echocardiographic and electrocardiographic evaluations as well as differentiation between fat and fat-free body mass have led to manifold innovative observations. Specifically, genetic and serological markers of the renin angiotensin system could be associated with high blood pressure and left ventricular hypertrophy. The same applies to the importance of parameters of body composition as obesity and muscular mass. Moreover, the prevalence of heart failure in the general population could be determined for the first time in Germany. Additionally, the prevalence of left ventricular systolic and diastolic dysfunction could be obtained in the region of the survey, exemplarily for the Federal Republic of Germany. Finally, the surveys of the population random sample were used to define normal serum levels of natriuretic peptides. In summary, the evaluation of cardiovascular phenotypes in the MONICA/KORA surveys resulted in a -- in the European region unique -- documentation of cardiovascular functional parameters in the general population. Moreover, multiple epidemiological observations as to pathophysiologically relevant topics of heart and vascular diseases could be studied in extraordinary details.

Cardiac safety of trastuzumab in combination with epirubicin and cyclophosphamide in women with metastatic breast cancer: results of a phase I trial.

This prospective, parallel-group, dose-escalation study evaluated the cardiac safety of trastuzumab (Herceptin) plus epirubicin/cyclophosphamide (EC) in women with human epidermal growth factor receptor-2 (HER2)-positive metastatic breast cancer (MBC) and determined an epirubicin dose for further evaluation. HER2-positive patients received standard-dose trastuzumab plus epirubicin (60 or 90 mg/m(2))/cyclophosphamide (600 mg/m(2)) 3-weekly (EC60+H, n=26; EC90+H, n=25), for four to six cycles; 23 HER2-negative patients received EC alone (90/600 mg/m(2)) 3-weekly for six cycles (EC90). All patients underwent thorough cardiac evaluation. Two EC90+H-treated patients experienced symptomatic congestive heart failure 4.5 and 6 months after the end of chemotherapy. One EC60+H-treated patient experienced an asymptomatic decrease in left ventricular ejection fraction (LVEF) to <50% 6 months after the end of chemotherapy. No such events occurred in control patients. Asymptomatic LVEF decreases of >10% points were detected in 12 (48%), 14 (56%) and 5 (24%) patients treated with EC60+H, EC90+H, and EC90. Objective response rates with EC60+H and EC90+H were >60%, and 26% for EC90 alone. These results indicate that trastuzumab may be combined with EC with manageable cardiotoxicity and promising efficacy.

Anthracycline and trastuzumab in breast cancer treatment.

This study was designed to evaluate the cardiac safety of the combined treatment of HER2-positive metastatic breast cancer patients with trastuzumab (Herceptin) plus epirubicin and cyclophosphamide (EC) in comparison with EC alone in HER2-negative metastatic breast cancer patients. Patients included those with metastatic breast cancer without any prior anti-HER2 treatment, anthracycline therapy, or any other chemotherapy for metastatic disease. This was a nonrandomized, prospective, dose-escalating, multicenter, open-label, phase I study in Germany. A control group of 23 patients received EC 90/600 mg/m2 3-weekly for six cycles (EC90 alone). A total of 26 HER2-positive patients were treated with trastuzumab, or H (2 mg/kg weekly after an initial loading dose of 4 mg/kg), and EC 60/600 mg/m2 3-weekly for six cycles (EC60+H); another 25 HER2-positive patients received H and EC 90/600 mg/m2 3-weekly for six cycles. Asymptomatic reductions in left ventricular ejection fraction (LVEF) of more than 10% points were detected in 12 patients (48%) treated with EC60+H and in 14 patients (56%) treated with EC90+H vs 6 patients (26%) in the EC90 alone cohort. LVEF decreases to <50% occurred in one patient in the EC60+H cohort and in two patients in the EC90+H cohort during the H monotherapy. No cardiac event occurred in the cohort with EC90 alone. The overall response rates for EC60+H and EC90+H were >60%, vs 26% for EC90 alone. The interim results of this study approve the cardiac safety of the combination of H with EC, with low risk of cardiac toxicity. The combination regimen revealed promising efficacy.

[Epidemiology of left ventricular systolic dysfunction in the general population of Germany: results of an echocardiographic study of a large population-based sample]. / Epidemiologie der linksventrikulären systolischen Dysfunktion in der Allgemeinbevölkerung Deutschlands. Ergebnisse echokardiografischer Untersuchungen einer grossen Bevölkerungsstichprobe.

The prevalence of left ventricular systolic dysfunction (LVSD) in the general population is poorly defined. Specifically, the number of asymptomatic individuals with LVSD and, thus, the most appropriate strategy to identify and treat such subjects is still unknown. Therefore, the aim of this study was to document LV dysfunction in a middle-aged (25 to 75 years, mean 51.8+/-13.8) population - based sample in Germany (MONICA Augsburg, n=1678; echocardiography technically adequate n=1418) by M-mode and 2D-echocardiography and to analyze the importance of predisposing contributors. The overall prevalence of an ejection fraction (EF) less than 48% (mean minus 2 SD=LVSD) was 2.3% (n=33), with a slightly higher rate in men than in women (2.8% vs 1.9%, n.s.). LVSD rate increased with age: from 1.5% in individuals younger than 40 years to 4.0% among those older than 60 years of age (p<0.05). Of 33 participants with reduced left ventricular systolic function, 20 presented with at least one cardiovascular disease. The most frequent diagnoses were arterial hypertension, obesity and coronary heart disease. Only 13 subjects (0.9%) of the study population were asymptomatic without a history of cardiovascular disease. Furthermore, only 6 subjects (0.4%, 4 male) in this population presented with a moderate impairment of LV function (EF of 30 to 40%) and only 1 subject (0.07%, male) had severe LVSD (EF less than 30%). Almost all subjects with an EF less than 40% (6 of 7 individuals) had a known history of cardiovascular disease. In conclusion, LVSD is a relatively common finding in the general population. However, severe LVSD is rare in subjects without any concomitant cardiovascular disease. Thus, echocardiographic screening cannot be recommended in the unselected, middle-aged population to identify such patients.

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.

[Ultrasonography of the inferior vena cava (IVC) in the diagnosis and monitoring of therapy in patients with chronic congestive heart failure]. / Sonographie der Vena cava inferior (VCI) zur Diagnostik und Therapiekontrolle bei chronischer Stauungs-Herzinsuffizienz.

OBJECTIVE: This prospective clinical study investigated whether the relatively simple and cost-effective ultrasonography of the inferior vena cava (IVC) represents a valid clinical tool to assess the effectiveness of diuretic therapy in patients with chronic congestive heart failure (CHF). METHODS: Measurement of the resting and inspiratory diameter of the VCI repeatedly during diuretic therapy in 23 consecutive patients (11 women, 70 +/- 10 years) with CHF and comparing the results to the daily measured body weight and serum creatinine in these patients. Results were compared with the IVC diameter obtained in 33 healthy controls (16 women, 42 +/- 15 years). In addition, the IVC collapse index was calculated to assess inspiratory movements of the IVC in patients on day 1 and 10 of therapy. RESULTS: The IVC diameter at rest was 2.4 +/- 0.6 cm and decreased to 2.0 +/- 0.7 cm at inspiration, which was significantly greater than in healthy controls (1.4 +/- 0.4 cm at rest and 1.05 +/- 0.5 cm at inspiration; p = 0.008 and p = 0.01, respectively). The IVC diameter decreased continuously and significantly (p < 0.003) from day 1 to day 10 during diuretic therapy without a concomitant rise in serum creatinine. At beginning of therapy, the collapse-index of the IVC was significantly greater in patients than in controls. However, after 10 days of therapy this index reached similar values to those observed in controls. CONCLUSION: Ultrasonographic measurements of IVC diameter and inspiratory movements are a quantifiable and reliable approach to assess the hypervolemia associated with CHF. Normalization of inspiratory IVC collapse movement correlates with successful diuretic therapy and can be reliably used for bedside assessment and monitoring treatment in CHF patients.

Indexation of left ventricular mass in adults with a novel approximation for fat-free mass.

BACKGROUND: Indexation to fat-free mass (FFM) seems to be the best option for adjusting left ventricular (LV) mass. However, measurements of FFM are frequently not available. OBJECTIVES: To define the relation of FFM with commonly available anthropometric measures in order to derive an approximation formula of FFM that can be used for valid indexation of LV mass. SUBJECTS AND METHODS: A total of 1,371 subjects from a community survey were examined by echocardiography to measure LV mass and by bioelectrical impedance analyses (BIA) for the determination of FFM. An approximation of FFM was generated in a healthy subgroup of 213 men and 291 women by non-linear regression techniques. RESULTS: Compared with body height, height2.0, height2.7, (the superscripts following weight and height are raised powers used as a more appropriate method for indexing LV mass) or body surface area, FFM measured by BIA in the healthy subgroups was best predicted by gender-specific equations of the form: FFM = 5.1 x height1.14 x weight0.41 for men and FFM = 5.34 x height1.47 x weight0.33 for women. In the healthy reference group, indexation of LV mass for BIA-determined FFM and approximated FFM (FFMa), respectively, equally eliminated gender differences in LV mass and markedly reduced the influence of body mass index without affecting the associations between blood pressure and LV mass. Validation of FFMa in two independent population-based samples, aged 52 to 67 years, of the same source population confirmed that LV mass indexed by FFMa produced results that were highly consistent with those obtained with indexation by BIA-determined FFM. CONCLUSIONS: We propose a novel approximation of FFM based on exponentials of body height and weight. It performed well in the indexation of LV mass in middle-aged men and women of this study. Evaluation of the equation in other populations should be awaited before its use is recommended in situations where direct determination of FFM is not possible.

Haematocrit profoundly affects left ventricular diastolic filling as assessed by Doppler echocardiography.

BACKGROUND: The main determinants of diastolic function--pre- and afterload of the heart--are affected by the haematocrit, but the relation between haematocrit and diastolic function is unclear. OBJECTIVE: To study the association between interindividual haematocrit values and diastolic function, by echocardiography. DESIGN: In a cross-sectional survey, blood pressure, haematocrit values, and high-quality Doppler indexes of left ventricular filling were obtained in 1297 individuals, 25-74 years of age, and analysed by regression analyses. RESULTS: Haematocrit and systolic blood pressure were strongly correlated (r = 0.23; P < 0.0001). Moreover, haematocrit was inversely correlated with the peak velocity of early left ventricular filling and with the peak velocity of early filling divided by late filling (E/A ratio; both P< 0.005). Left ventricular isovolumic relaxation time (IVRT) was positively associated with haematocrit (r= 0.18, P< 0.001). In individuals with an abnormal Doppler filling pattern (E/A(< 50 years) < 1, E/A(> 50 years) < 0.5, or IVRT(< 30 years) > 92 ms, IVRT30-50 years > 100 ms or IVRT> 50 years > 1 05 ms; n = 119), greater haematocrit values were observed than in those with normal diastolic parameters (P< 0.001). Conversely, individuals with an increased haematocrit (> 50% in men, > 45% in women; n = 16) had a greater risk of presenting with abnormal left ventricular filling (31.3%) compared with individuals with normal (12.1%; n = 898;) or low (< 40% in men, < 35% in women: 10.5%, n = 38; P = 0.07) haematocrit. Strong and significant associations between haematocrit and Doppler indexes of left ventricular filling were confirmed after adjustment for multiple potential confounders including blood pressure, antihypertensive medication and body mass index. Similarly, blood pressure and parameters of diastolic filling were strongly associated correlations that were not affected by inclusion of haematocrit values into the regression model. CONCLUSION: The data point to substantial adaptations of diastolic filling in response to both blood pressure and the characteristics of the medium that is propelled by the heart Therefore, in addition to blood pressure values, the variability of haematocrit values should be considered when diastolic function is being evaluated by Doppler echocardiography.

Body composition and prevalence of left ventricular hypertrophy.

BACKGROUND: Fat-free mass (FFM) has been proposed as an optimal normalization of left ventricular (LV) mass to body size. We sought to evaluate the novel FFM-based criteria of LV hypertrophy (LVH). METHODS AND RESULTS: A population sample of 1371 men and women aged 25 to 74 years was examined by echocardiography and bioelectrical impedance analysis. Internal partition values for LVH were generated in a healthy population subgroup on the basis of LV mass divided by FFM and by the traditional indexations to body height, height(2.7), and body surface area. In contrast to the sex-specific criteria required by traditional indexations, the value of LV mass/FFM that divided individuals with and without LVH was identical for men and women (4.1 g/kg). Estimates of LVH prevalence varied significantly by type of indexation used, internally or externally derived cut points, and by population subgroups. Differences were pronounced among hypertensives and the obese. Thus, the application of LV mass/FFM more than halved the risk of LVH in obese versus nonobese women (odds ratio, 2.5; 95% confidence interval, 1.6 to 4.0) compared with criteria based on LV mass/height(2.7) (odds ratio, 5.5; 95% confidence interval, 3.6 to 8.3). Implications among hypertensives were less marked. CONCLUSIONS: Indexation of LV mass to FFM eliminates sex-specific LVH criteria. The proportion of individuals defined as having LVH using the new criteria deviate markedly from traditional indexations. Prospective investigations will be needed to identify the prognostic implications of different indexations, especially in subgroups such as the obese.

Familial predisposition of left ventricular hypertrophy.

OBJECTIVES: The study evaluated the contribution of familial predisposition to the risk of left ventricular hypertrophy (LVH). BACKGROUND: Left ventricular hypertrophy is a multifactorial condition that serves as an important predictor of cardiovascular mortality. At present it is unclear whether familial predisposition contributes to the manifestation of LVH. Thus, we determined whether siblings of subjects with LVH are at increased risk to present with an elevation of LV mass or an abnormal LV geometry. METHODS: Echocardiographic and anthropometric measurements were performed in 2,293 individuals who participated in the echocardiographic substudies of population-based MONICA Augsburg surveys. In addition, a total of 319 siblings of survey participants with echocardiographic evidence of LVH were evaluated. The risk of these siblings to present with LVH or abnormal LV geometry was estimated by comparison with 636 subjects matched for gender and age that were selected from the entire echocardiography study base. RESULTS: Blood pressure, body mass index, age, and gender (i.e., known determinants of LV mass) were comparable in LVH-siblings and the matched comparison group. However, septal and posterior wall thicknesses, relative wall thickness as well as LV mass index were significantly elevated in LVH-siblings (p < 0.001, each) whereas LV dimensions did not differ. Likewise, the prevalence of LVH was raised in LVH-siblings, as was the relative risk of LVH after adjustment for confounders (p < 0.05). More specifically, LVH-siblings displayed increased prevalences of concentric remodeling and concentric LVH (p < 0.05) but not of eccentric LVH. CONCLUSIONS: Familial predisposition appears to contribute to increased LV wall thickness, to the development of LV hypertrophy and abnormal LV geometry.

Lack of association between a polymorphism of the aldosterone synthase gene and left ventricular structure.

BACKGROUND: Cardiac growth and function may be modulated in part by trophic effects of neurohormones. Specifically, aldosterone has been shown to stimulate the growth of cardiac myocytes and the accumulation of cardiac extracellular matrix proteins. Moreover, a variant of the aldosterone synthase gene (a cytosine/thymidine exchange at position -344 in the transcriptional regulatory region) has been associated with enlargement and disturbed filling of the left ventricle (LV) in a small sample of young white adults. The aim of the present study was to reinvestigate the implications of aldosterone synthase -344C/T allele status for serum aldosterone levels, blood pressure, and LV structure and function in large population-based samples. METHODS AND RESULTS: Individuals who participated in the echocardiographic substudy of the third MONICA (MONitoring trends and determinants in CArdiovascular disease) survey (n=1445) or in the second follow-up of the first MONICA survey (n=562) were studied by standardized anthropometric, echocardiographic, and biochemical measurements as well as genotyping for aldosterone synthase -344C/T allele status. In both surveys, the distribution of sex, age, arterial blood pressure, and body mass index was homogeneous in the aldosterone synthase genotype groups. Echocardiographic LV wall thicknesses, dimensions, and mass indexes were not significantly associated with a specific aldosterone synthase genotype. Likewise, no association was detectable with echocardiographic measures of LV systolic or diastolic function. Data were consistent in both samples and not materially different in subgroups defined by age, sex, or intake of antihypertensive medication. Finally, no significant association was observed for aldosterone synthase allele status and serum aldosterone levels in the group of 562 individuals. CONCLUSIONS: The data are not in favor of a significant contribution of the C/T exchange at position -344 in the aldosterone synthase transcriptional regulatory region to the variability of serum aldosterone levels, blood pressure, or cardiac size or function as found in 2 white population-based samples.

Gender specific differences in left ventricular adaptation to obesity and hypertension.

Recent reports indicate that the prognostic implications of left ventricular hypertrophy (LVH) are more profound in women than in men. The prognosis of LVH is also related to the underlying geometric pattern. We therefore assessed the relation of separate and concurrent influences of obesity and hypertension on gender-specific patterns of LV adaptation. Five hundred and twenty participants of a community-based study (aged 52 to 67 years) were examined by M-mode echocardiography. Study subjects were divided into four groups: normals, obese, hypertensives, and subjects presenting with both obesity and hypertension. The groups were compared for various measures of left ventricular mass (LVM) and geometry. Relative to normal subjects, the increments in wall thickness, ventricle diameters, and LVM were all significant and of similar magnitude for obese men and women. Likewise, hypertensive men and women showed similar relative increments of LVM and wall thickness but no changes in end-diastolic internal diameters. Accordingly, obesity was predominantly associated with eccentric hypertrophy (men +/- 14%, women +17%, P<0.05 vs normals) and hypertension with concentric hypertrophy (men +16%, women +30%, P<0.01 vs normals). Women with concurrent obesity and hypertension presented with a further increase of LVM and wall thickness above values in the merely obese or hypertensive (P<0.001) and they displayed LVH more frequently than only obese or hypertensive women (P<0.05). We conclude that the hearts of postmenopausal women respond more susceptibly to the concurrence of hypertension and obesity. In particular the prognostically less favourable concentric LVH is a common finding. Our study may help to explain the higher risk associated with LVH in women.

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.

Assessment of left ventricular diastolic filling in arterial hypertension: comparison of pulsed Doppler echocardiography and acoustic quantification.

We compared acoustic quantification (AQ) to Doppler echocardiography (DE) in the evaluation of left ventricular (LV) diastolic filling in 41 hypertensives and 42 controls. In hypertensives, DE showed reduced ratios of early to late diastolic velocity, AQ revealed reduced peak to late filling rate ratios, and both techniques found prolonged acceleration times indicating abnormal filling. In 22 patients with mild hypertension and less LV hypertrophy, however, all DE filling parameters were normal. In these patients AQ indicated prolonged acceleration times and early filling times. In conclusion, AQ is useful for the identification of abnormal LV filling in arterial hypertension and might be superior to DE in detection of early diastolic dysfunction.

Changes in left ventricular structure and function in patients with white coat hypertension: cross sectional survey.

OBJECTIVES: To assess the relation between white coat hypertension and alterations of left ventricular structure and function. DESIGN: Cross sectional survey. SETTING: Augsburg, Germany. SUBJECTS: 1677 subjects, aged 25 to 74 years, who participated in an echocardiographic substudy of the monitoring of trends and determinants in cardiovascular disease Augsburg study during 1994-5. OUTCOME MEASURES: Blood pressure measurements and M mode, two dimensional, and Doppler echocardiography. After at least 30 minutes' rest blood pressure was measured three times by a technician, and once by a physician after echocardiography. Subjects were classified as normotensive (technician <140/90 mm Hg, physician <160/95 mm Hg; n=849), white coat hypertensive (technician <140/90 mm Hg, physician >=160/95 mm Hg; n=160), mildly hypertensive (technician >=140/90 mm Hg, physician <160/95 mm Hg; n=129), and sustained hypertensive (taking antihypertensive drugs or blood pressure measured by a technician >=140/90 mm Hg, and physician >=160/95 mm Hg; n=538). RESULTS: White coat hypertension was more common in men than women (10.9% versus 8.2% respectively) and positively related to age and body mass index. After adjustment for these variables, white coat hypertension was associated with an increase in left ventricular mass and an increased prevalence of left ventricular hypertrophy (odds ratio 1.9, 95% confidence interval 1.2 to 3.2; P=0.009) compared with normotensive patients. The increase in left ventricular mass was secondary to significantly increased septal and posterior wall thicknesses whereas end diastolic diameters were similar in both groups with white coat hypertension or normotension. Additionally, the systolic white coat effect (difference between blood pressures recorded by a technician and physician) was associated with increased left ventricular mass and increased prevalence of left ventricular hypertrophy (P<0.05 each). Values for systolic left ventricular function (M mode fractional shortening) were above normal in subjects with white coat hypertension whereas diastolic filling and left atrial size were similar to those in normotension. CONCLUSION: About 10% of the general population show exaggerated inotropic and blood pressure responses when mildly stressed. This is associated with an increased risk of left ventricular hypertrophy.

Neurohormonal activity and left ventricular geometry in patients with essential arterial hypertension.

The purpose of this study was to investigate whether the basal activity of the renin-angiotensin-aldosterone system or the basal levels of the atrial natriuretic peptide (ANP) are related to distinct patterns of left ventricular (LV) geometry in patients with essential hypertension. The left ventricle of patients with arterial hypertension may be exposed to a variety of growth-regulating mechanisms, including pressure overload and humoral activation. The interaction of such growth stimuli may be involved in the modulation of LV geometry. LV geometry was determined echocardiographically in 104 patients with mild to moderate essential hypertension. The same number of age- and sex-matched normotensive subjects served as controls. Plasma renin activity (PRA) and serum concentrations of aldosterone and ANP were measured by radioimmunoassay. Correlation analyses revealed that PRA was significantly associated with septal wall thickness and LV mass index (r = 0.25; p < 0.005 each). In addition, as compared with normal subjects (1.0 +/- 0.7 ng/ml/hr), PRA was significantly increased in patients with concentric LV hypertrophy (LVH) (3.4 +/- 6.6 ng/ml/hr, p < 0.01). Aldosterone displayed a close correlation with septal, posterior, and relative wall thickness (r > 0.27, p < 0.005 each). Compared with normal subjects (74 +/- 27 pg/ml), patients with hypertension and pathologic patterns of LV geometry were characterized by elevations of aldosterone (LV remodeling 203 +/- 93 pg/ml, concentric LVH 123 +/- 67 pg/ml; eccentric LVH 199 +/- 89 pg/ml; p < 0.05 each). ANP was significantly associated with septal wall thickness, left ventricular dimension, and LV mass index (r > 0.22, p < 0.005 each). Furthermore, compared with normal subjects (50 +/- 17 pg/ml), ANP values were significantly increased in patients with hypertension and concentric LVH (80 +/- 44 pg/ml, p < 0.005) and eccentric LVH (88 +/- 24 pg/ml, p < 0.001). Multivariate analysis adjusting for systolic blood pressure, body mass index, and age revealed that renin and ANP were independently associated with LV mass index (p < 0.05 each). Interestingly, adjusted PRA levels were not related to any specific pattern of LV geometry. In contrast, adjusted ANP levels were associated with concentric and eccentric LVH, whereas adjusted aldosterone levels were significantly elevated in subjects with LV remodeling and eccentric LVH (p < 0.005). Thus elevated levels of renin and ANP may be found in patients with hypertension and elevated LV mass index. In addition, ANP and aldosterone are related to specific geometric patterns of the left ventricle. The data may further stimulate the discussion on the mechanisms that account for alterations of LV geometry in hypertension.

Differential effects of antihypertensive drugs on neurohormonal activation: insights from a population-based sample.

OBJECTIVES: The clinical course of hypertension or heart failure may be modified by the extent of concurrent neurohormonal activation. Factors that regulate neurohormones in patients with these conditions are complex. In the present study, we examined the relative contribution of antihypertensive therapy to the variability of neurohormonal levels in a well defined population based sample. DESIGN AND SETTING: Cross-sectional study of a mixed urban and rural population. SUBJECTS: Middle-aged individuals (n = 646) were analysed in order to elucidate determinants of neurohormone levels by uni- and multivariate comparisons. The assessment included anthropometric, echocardiographic and, if appropriate, genotype information. RESULTS: The intake of antihypertensive drugs was related to significant alterations of neurohormone levels that, in part, exceeded the contribution of all other variables studied. Multivariate analyses revealed that renin levels were independently related to the intake of beta blockers (n = 80; -8.4 mU L-1; P = 0.001), angiotensin-converting enzyme (ACE)-inhibitors (n = 39; +15.9 mU L-1; P = 0.0001), diuretics (n = 62; +14.3 mU L-1; P = 0.0001), and calcium channel blockers (n = 45; +5.9 mU L-1; P = 0.05). Aldosterone levels were related to ACE-inhibition (-156.5 pmol L-1; P = 0.04) and diuretic treatment (+422.4 pmol L-1; P = 0.0001) in an opposite fashion whereas beta blockers and calcium channel blockers had no significant independent effects. The levels of the atrial natriuretic peptide were significantly related to the use of beta blockers (+3.9 pmol L-1; P = 0.002) and calcium channel blockers (+3.1 pmol L-1; P = 0.05). Finally, serum angiotensinogen levels and ACE activity were not found to be significantly affected by antihypertensive medication but were rather related to gender or genotype. CONCLUSIONS: The data emphasize that antihypertensive treatment with different classes of drugs may modulate serum levels of neurohormones substantially resulting in distinct patterns of activation. These drug-related effects may require consideration when neurohormonal activation is of functional relevance or when neurohormones serve as prognostic predictors in patients with cardiovascular disorders.

Associations between circulating components of the renin-angiotensin-aldosterone system and left ventricular mass.

OBJECTIVE: Cardiac growth may be modulated in part by the trophic effects of neurohormones. The aim of the present study was to investigate the relation between the basal activity of the renin-angiotensin-aldosterone system and left ventricular mass. DESIGN: A population based sample of 615 middle-age subjects was studied by standardised echocardiography; anthropometric measurements; and biochemical quantification of renin, pro-renin, angiotensinogen, angiotensin converting enzyme (ACE), and aldosterone. RESULTS: Echocardiographic left ventricular mass index correlated significantly with arterial blood pressure, age, and body mass index. In addition, in men ACE activity was significantly related to left ventricular mass index in univariate (P = 0.0007) and multivariate analyses (P = 0.008). Men with left ventricular hypertrophy presented with significantly higher serum ACE concentrations than those with normal left ventricular mass index (P = 0.002). In both men and women serum aldosterone was strongly related to septal and posterior wall thickness. Furthermore, in women serum aldosterone was positively and independently associated with left ventricular mass index (P = 0.0001). This effect was most prominent in hypertensive women. Finally, women with left ventricular hypertrophy presented with significantly higher serum aldosterone (P = 0.01). No significant associations with left ventricular mass index were observed for angiotensinogen, renin, or pro-renin. CONCLUSIONS: The data suggest that the variability of serum ACE or aldosterone, as occurred in this large population based sample, may contribute to the modulation of left ventricular mass.