Anti-anginal and anti-ischemic effects of the selective beta-blocker talinolol in patients with stable angina pectoris.

OBJECTIVE: To determine the dose dependency of the anti-anginal and antiischemic effects of the selective beta-blocker talinolol administered once-daily in a randomized, double-blind, placebo-controlled multicenter study in patients with stable angina pectoris. METHODS: Standardized bicycle ergometry at baseline and after 3 and 6 weeks of treatment was used to assess exercise capacity. The primary endpoint was the change in the maximum exercise time (MET) 24 +/- 1 h after the last intake of study medication compared to baseline. Secondary efficacy parameters were time to onset of angina, time to 1 mm ST segment depression, angina attacks, consumption of short-acting nitrates, blood pressure and pulse rate. Patients were randomly allocated to treatment with talinolol (100, 200 or 300 mg once daily) or placebo for a period of 6 weeks. RESULTS: A total of 241 outpatients (204 male and 37 female) aged between 34 and 83 years, were randomized in 31 centers in Germany, Poland and the Czech Republic. At the end of treatment, the primary endpoint (change in MET compared to baseline) showed no significant difference between the talinolol groups and placebo. The means of MET prolongation ranged from 27.4 sec under placebo to a maximum of 47.6 sec in the 200 mg group. However, the time to 1 mm ST segment depression during exercise increased markedly with talinolol, the difference to placebo reaching statistical significance with the 200 mg/d dose (80.1 +/- 32.7 sec, p = 0.0182) and 300 mg/d dose (82.0 +/- 31.6 sec, p = 0.0127). In the case of the other secondary variables, the most pronounced effects were recorded for talinolol doses of 200 and 300 mg/d. Talinolol significantly inhibited the exercise-induced increase in heart rate and blood pressure. The decrease in rate pressure product at 100 W workload was statistically significant with all administered talinolol doses (delta from baseline to final visit 3090, 4351 and 4291 for 100, 200 and 300 mg/d, respectively, p < 0.0001). Despite once-daily dosing, talinolol at doses up to 300 mg/d was very well tolerated. No unexpected adverse drug reactions were observed. CONCLUSION: The results show that talinolol administered once daily in a dosage of 200 - 300 mg/d is effective and safe in the management of chronic stable angina.

Beta-2 adrenergic receptor gene variations and blood pressure under stress in normal twins.

We tested the hypothesis that blood pressure (BP) responses to physical and mental stress are associated with polymorphisms in the beta-2 adrenergic receptor (AR) gene. We studied normotensive, young, monozygotic (MZ) and dizygotic (DZ) twins. The subjects underwent automated BP measurements at the brachial and digital arteries and were subjected to mental arithmetic and cold pressor stress. We used allele-specific PCR to genotype four single nucleotide polymorphisms in the beta-2 AR gene. The most functionally relevant polymorphism in the beta-2 AR gene, Arg16/Gly, was associated with systolic and diastolic BP under resting conditions, during mental arithmetic, and during the cold pressor test, as well as with the increase in diastolic BP during both forms of stress. These findings support a role for the beta-2 AR gene in BP regulation. They also indicate that the beta-2 AR gene influences the level of not only resting but also stress-related BP.

[Nebivolol, a beta blocker of the 3rd generation: modern therapy of arterial hypertension. Results of a multicenter observation study]. / Nebivolol, ein Betablocker der 3. Generation: Die moderne Therapie der arteriellen Hypertonie. Ergebnisse einer multizentrischen Beobachtungsstudie.

BACKGROUND: Nebivolol represents a therapeutic class of beta blockers with high beta 1 selectivity and modulatory effect on vascular reactions by releasing nitric oxide (NO) from endothelial cells. Its antihypertensive effect by once a day application is established. The aim of the study was to investigate the acceptability and the antihypertensive efficacy of Nebivolol in hypertensives with and without concomitant diseases. METHODS AND RESULTS: An observational study was carried out in 6376 patients with arterial hypertension in 1529 centres in a period of time of six weeks. The initial dosage was 5 mg daily resp. 2.5 mg daily in patients over 65 years. The systolic blood pressure (BP) decreased during treatment from initial values of 173 +/- 18 mm Hg (mean +/- standard deviation) by 29 mm Hg to 144 +/- 14 mm Hg at the end of the observational period. The diastolic BP decreased from 101 +/- 9 mm Hg initially by 16 mm Hg to 85 +/- 8 mm Hg at the last examination of the patients. The normalization of the diastolic BP (< 90 mm Hg) was achieved in 62.2% of the patients. The mean heart rate (HR) was 84 +/- 12 beats/minute at the beginning of the study and decreased by 11 to 73 +/- 8 beats/minute. During the observational period cholesterol, triglycerides and blood glucose showed a significant decrease (p < 0.001). Triglycerides were diminished by 13%, cholesterol by 8%. In diabetic patients the most favourable effect was observed (decrease of triglycerides by 18% and cholesterol by 9%); glucose decreased in diabetics by 16%. CONCLUSIONS: In this multicentre observational study Nebivolol was proved as a safe and well-tolerated antihypertensive drug. The results of the analysis of metabolic parameters during Nebivolol treatment are of interest as a contribution to the preventive effect of this beta blocker on coronary heart disease.

Genetic influences on baroreflex function in normal twins.

Blood pressure and heart rate are strongly influenced by genetic factors; however, despite the pivotal role of genetics in short-term cardiovascular regulation, little is known about the genetic contribution to baroreflex function. We assessed genetic influence on baroreflex sensitivity (BRS) in 149 twin pairs (88 monozygotic of age 33+/-13 years and BMI 23+/-4 kg/m(2) and 61 dizygotic of age 33+/-11 years and BMI 24+/-4 kg/m(2)). ECG and finger arterial blood pressures were measured continuously under resting conditions. BRS values were calculated by use of cross-spectral analysis (baroreflex slope calculated as mean value of transfer function between systolic blood pressure and the R-R interval in the low-frequency band [BRSLF] and baroreflex slope calculated as the mean value of transfer function between systolic blood pressure and R-R interval in the respiratory frequency band [BRSHF]) and the sequence technique (BRS+, BRS-). Heritability (h(2)) was estimated with a path-modeling approach. BRS values did not differ significantly between groups (monozygotic, BRSLF, 17+/-13; BRSHF, 21+/-18; BRS+, 19+/-16; and BRS-, 21+/-15, and dizygotic, BRSLF, 16+/-9; BRSHF, 20+/-14; BRS+, 18+/-10; and BRS-, 20+/-11 ms/mm Hg), and were significantly correlated (P:<0.001). When variances and covariances for monozygotic and dizygotic twins were compared, significant correlations were found for BRS in monozygotic (range, r=0.38 to 0.48) but not in dizygotic twin pairs (r=-0.03 to 0.09). Thus, BRS is heritable; the variability can be explained by genetic influences (P:<0.01; h(2) range, 0.36 to 0.44). The genetic influence on BRS remained strong after correction for BMI and blood pressure. Therefore, BRS is strongly genetically determined, probably by different genes than are resting blood pressure and BMI.

beta-2 adrenergic receptor gene variations, blood pressure, and heart size in normal twins.

Genetic variability, which influences cardiovascular phenotypes in normal persons, is likely to be relevant to cardiovascular disease. We studied normal monozygotic and dizygotic twins and found strong genetic influences on blood pressure and heart size. We then relied on the dizygotic twins and their parents to apply molecular genetic techniques. We performed a linkage analysis with markers close to the beta-2 adrenergic receptor (AR) gene locus in the dizygotic twins and their parents and found strong evidence for linkage to the quantitative traits of blood pressure and heart size. We then used allele-specific polymerase chain reaction to genotype the subjects further. We performed an association analysis and found that 4 functionally relevant polymorphisms in the beta-2 AR gene, namely Arg16/Gly, Gln27/Glu, Thr164/Ile, and a variant in the promoter region (-47C/T), were variably associated with blood pressure and heart size differences but were in linkage dysequilibrium with each other. A subsequent conditional analysis suggested that the Arg16/Gly polymorphism exerted the predominant effect. These findings underscore the importance of the beta-2 AR gene to blood pressure regulation, heart size, and probably to the development of hypertension. We suggest that a combined linkage and association approach will elucidate the genetic variability influencing blood pressure and other cardiovascular phenotypes.

A cholesterol-lowering gene maps to chromosome 13q.

A cholesterol-lowering gene has been postulated from familial hypercholesterolemia (FH) families having heterozygous persons with normal LDL levels and homozygous individuals with LDL levels similar to those in persons with heterozygous FH. We studied such a family with FH that also had members without FH and with lower-than-normal LDL levels. We performed linkage analyses and identified a locus at 13q, defined by markers D13S156 and D13S158. FASTLINK and GENEHUNTER yielded LOD scores >5 and >4, respectively, whereas an affected-sib-pair analysis gave a peak multipoint LOD score of 4.8, corresponding to a P value of 1.26x10-6. A multipoint quantitative-trait-locus (QTL) linkage analysis with maximum-likelihood binomial QTL verified this locus as a QTL for LDL levels. To test the relevance of this QTL in an independent normal population, we studied MZ and DZ twin subjects. An MZ-DZ comparison confirmed genetic variance with regard to lipid concentrations. We then performed an identity-by-descent linkage analysis on the DZ twins, with markers at the 13q locus. We found strong evidence for linkage at this locus with LDL (P<.0002), HDL (P<.004), total cholesterol (P<.0002), and body-mass index (P<.0001). These data provide support for the existence of a new gene influencing lipid concentrations in humans.

[Nebivolol, a third generation beta blocker: the modern treatment of hypertension. Results of a multicentric observational study]. / Nebivolol, ein Betablocker der dritten Generation: Die moderne Therapie der arteriellen Hypertonie. Ergebnisse einer multizentrischen Beobachtungsstudie.

BACKGROUND: Nebivolol represents a new therapeutic class of beta blockers with high beta1 selectivity and the ability to modu late the direct vascular reactions through the liberation of nitric oxide (NO) by the endothelial cell. Its antihypertensive action develops at a once-daily dosage. The main aim of the study was to determine the tolerability and antihypertensive efficacy of nebivolol in hypertensives with or without concomitant diseases. METHODS AND RESULTS: The observational study was carried out in 1529 centers on 6376 patients with hypertension over a period of 6 weeks. The initial daily dosage was 5 mg or 2.5 mg in patients older than 65. Under treatment, the systolic blood pressure decreased by a mean (+/- 1 standard deviation) of 29 mmHg (+/- 17 mmHg) from 173 mmHg (+/- 18 mmHg) initially, to 144 mmHg (+/- 14 mmHg) by the end of the observation period. The diastolic blood pressure decreased by a mean of 16 mmHg (+/- 10 mmHg) from 101 mmHg (+/- 9 mmHg) initially to 85 mmHg (+/- 8 mmHg) by the end of the observation period (p < 0.001). Normalization of the diastolic blood pressure (< 90 mmHg) was achieved in 62.2% of the patients. The mean heart rate at the start of the study was 84 (+/- 12) vs. 73 (+/- 8) beats per minute by the end of the study (reduction: 10.6 +/- 10.3 beats per minute). The decrease in blood pressure and heart rate depended on the baseline values, that is, higher blood pressure and higher heart rates initially showed a greater reduction (both parameters) in comparison with moderately elevated initial values. Cholesterol, triglycerides and blood sugar decreased significantly (p < 0.001) duringthe observation period. For triglycerides the decrease was 13%, for cholesterol 8%. Diabetics benefited most (reduction in triglycerides 18%, in cholesterol 9%); here, the glucose concentration decreased by 16%. Physician-assessment of the efficacy of nebivolol was 93%, tolerability 97% (very good or good). CONCLUSION: In this large multicentric observational study, the substance nebivolol proved to be a safe, largely side effect-free antihypertensive. Its favorable metabolic properties must be considered positive, in particular with regard to the possible development of coronary heart disease.

Peroxisome proliferator-activated receptor gamma gene locus is related to body mass index and lipid values in healthy nonobese subjects.

The peroxisome proliferator-activated receptor gamma (PPARgamma) gene has been implicated in morbid obesity and is important to lipid and carbohydrate metabolism. However, the relevance of gene variations in healthy nonobese subjects has not been defined. We recruited monozygotic and dizygotic healthy nonobese twin subjects to test the hypothesis that the PPARgamma gene is important to body mass index and lipid concentrations in healthy nonobese subjects. Both linkage and association strategies were used in the same dizygotic twins. The PPARgamma gene locus was linked (P<0.01) to high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and body mass index as quantitative traits. A biallelic variant in the PPARgamma gene was associated with high-density lipoprotein cholesterol and body mass index (P<0.05). We also looked for linkage between the same variables and the retinoic X receptor gene locus. This locus was linked to total and low-density lipoprotein cholesterol as well as triglycerides. We conclude that the PPARgamma gene is highly relevant to lipid metabolism and body mass index, not only in the morbidly obese but also in healthy nonobese subjects. The same appears to be true for its binding partner. Sequencing these genes in twins would serve to identify gene variations contributing to body mass index and lipid concentrations in healthy nonobese subjects.

Linkage but lack of association for blood pressure and the alpha-adducin locus in normotensive twins.

BACKGROUND: alpha-adducin is a cytoskeletal protein involved with sodium-pump activity in the renal tubule. The alpha-adducin gene locus has been linked to hypertension and a polymorphism identified which is associated with hypertension; however, the role of the alpha-adducin gene locus in normal blood pressure regulation is not defined. We performed a combined linkage and association study in normotensive monozygotic (MZ) and dizygotic (DZ) twins and their parents to address this issue. METHODS: We studied 126 MZ and 70 DZ twin pairs and parents of DZ twins. Blood pressure values and responses to a cold pressor test were obtained. Cardiac dimensions were measured echocardiographically. Three microsatellites adjacent to the alpha-adducin gene were studied as well as the 460 Trp mutation in the alpha-adducin gene. RESULTS: We obtained strong evidence for linkage (P< 0.001) between the alpha-adducin gene locus and systolic blood pressure. However, we were not able to associate the 460 Trp mutation with higher blood pressures, cold pressor responses or cardiac dimensions. CONCLUSIONS: The alpha-adducin gene locus is relevant to blood pressure regulation in normal subjects. Failure to find an association between higher blood pressures and the 460 Trp mutation suggests that this mutation may become important only when hypertension is triggered, or that other variations in alpha-adducin are present which have not yet been discovered.

Quantitative trait loci for blood pressure exist near the IGF-1, the Liddle syndrome, the angiotensin II-receptor gene and the renin loci in man.

Blood pressure (BP) is heritable and finding quantitative trait loci that influence BP is an important step in identifying genes responsible for BP regulation. Sixty-six pairs of dizygotic (DZ) twin subjects and their parents were used in a sib-pair analysis to look for linkage of selected candidate genes to the quantitative trait BP. Microsatellite markers were tested in the vicinity of the gene loci for insulin-like growth factor-1 (IGF-1), Liddle syndrome, autosomal-dominant hypertension with brachydactyly, angiotensinogen, angiotensin II type 1 receptor, angiotensin-converting enzyme, renin, and lipoprotein lipase. BP was measured in a standardized manner. Heart size was determined echocardiographically. Significant linkage was found at the IGF-1, Liddle syndrome, and AT1 receptor gene for systolic BP. Linkage for diastolic BP was found at the autosomal-dominant hypertension with brachydactyly locus. Both systolic and diastolic BP were linked to the renin gene locus. The linkage was most consistent for the IGF-1 gene locus and systolic BP. Linkage was also found between the IGF-1 gene locus and posterior cardiac wall thickness, septal thickness, and left ventricular mass index. It is suggested that these quantitative trait loci may be important for the subsequent detection of allelic variants for elevated BP. Furthermore, these results linking the IGF-1 gene locus to both BP and cardiac dimensions underscore the importance of the IGF-1 gene as a candidate gene for cardiovascular disease.

Genetic and environmental influences on coping styles: a twin study.

OBJECTIVE: Coping styles are generally considered to be environmentally driven, primarily by family influences. However, because personality traits are commonly influenced by genetic effects, we hypothesized that heredity is also important for coping. METHODS: We tested this hypothesis by assessing 19 coping styles, as well as four secondary coping factors, by questionnaire in 212 pairs of monozygotic and dizygotic twins. We then examined heredity by structural equation modeling. RESULTS: All coping styles showed evidence of genetic influences. The coping styles shared one common genetic factor. In addition, each coping style was also influenced by other separate genetic factors. Shared environment had no significant influence on coping styles. Three of 19 more specific coping styles showed shared environmental effects as well as genetic influences, 14 were solely under genetic influences, and two showed only shared environment effects. CONCLUSIONS: We suggest that hereditary effects on certain coping style preferences cannot be explained solely by genetic influences on major personality traits and temperament. An analysis of the relationships between coping and personality in twin subjects may elucidate the distinction between genetic and environmental effects.

QT interval is linked to 2 long-QT syndrome loci in normal subjects.

BACKGROUND: The rate-corrected QT interval (QTc) is heritable, and the discovery of quantitative trait loci that influence the QTc would be an important step in identifying the genes responsible for life-threatening arrhythmias in the general population. We studied 66 pairs of unselected normal dizygotic (DZ) twin subjects and their parents in a sib-pair analysis. We tested for linkage of gene loci harboring genes known to cause the long-QT syndrome (LQT) to the quantitative trait QTc. METHODS AND RESULTS: We found genetic variance on QRS duration, QRS axis, T-wave axis, and QTc. Women had a longer QTc than men. Microsatellite markers were tested in the vicinity of the gene loci for the 5 known LQT genes. We found significant linkage of QTc with the loci for LQT1 on chromosome 11 and LQT4 on chromosome 4 but not to LQT2, LQT3, or LQT5. We also found linkage of the QRS axis with LQT2 and LQT3. CONCLUSIONS: We suggest that these quantitative trait loci may represent the presence of variations in LQT genes that could be important to the risk for rhythm disturbances in the general population.

Chymase gene locus is not associated with myocardial infarction and is not linked to heart size or blood pressure.

The chymase gene is said to be important for the generation of angiotensin II in the heart and therefore is a candidate gene for heart disease. However, we were unable to find an association between allelic variants of the chymase gene and acute myocardial infarction or linkage between the chymase gene locus and heart size.

Treatment of high blood pressure in Germany.

The reunification of Germany has made it possible to compare the health care in two independently developed social structures. The prevalence of hypertension was considerably greater in East German men and women, compared with West German men and women, although salt intake was lower in East Germany than in West Germany. Cardiovascular mortality was correspondingly greater. A centralized public health effort was used in East Germany, whereas in West Germany, the activities were decentralized and to a large extent dependent on private philanthropists. In the last two decades, cardiovascular mortality declined in West German men and women, whereas the same was not true for East German men and women. Hypertension incidence, awareness, treatment, and control have improved slightly in Germany, but not enough to explain the improved morbidity figures. Twenty percent of men and women remain unaware of their hypertension, 40% are aware but not treated, and only half are aware and controlled. Complacency is unjustified in Germany and much needs to be done.

Angiotensin-converting enzyme and angiotensinogen gene polymorphisms and heart rate variability in twins.

Decreased heart rate variability (HRV) is associated with congestive heart failure, post-myocardial infarction, ventricular arrhythmias, sudden cardiac death, and advancing age. A deletion/insertion polymorphism in the angiotensin-converting enzyme (ACE) gene and a substitution (M235T) in the angiotensinogen gene have been associated with risk for heart disease. The aim of this study was to determine the heritability of HRV and related parameters in monozygotic and dizygotic twins and to assess the influence of ACE and angiotensinogen polymorphisms. We studied 95 MZ pairs and 46 DZ pairs. We measured HRV and related parameters, ACE and angiotensinogen levels, plasma norepinephrine, ACE, and angiotensinogen genotypes. We found that HRV and related parameters were significantly influenced by genetic variability, although nonshared genetic effects were also important. Angiotensinogen and plasma norepinephrine were generally correlated with decreased HRV, whereas ACE was correlated with perturbances of normal rhythmic HRV. Nevertheless, the DD ACE genotype was associated with increased HRV (p <0.05), whereas angiotensinogen polymorphisms had no effect. We conclude that HRV and related parameters are in part heritable. Interestingly, the DD ACE genotype is associated with increased HRV.

Heritability analysis of lipids and three gene loci in twins link the macrophage scavenger receptor to HDL cholesterol concentrations.

We studied 100 healthy monozygotic and 72 dizygotic twin pairs (mean age, 34 +/- 14 years) to test for genetic influences on blood lipids and to examine relevant gene loci. Total cholesterol (TC), LDL cholesterol (LDL-C), HDL cholesterol (HDL-C), and triglyceride (TG) levels were determined after a 12-hour fast. Zygosity was determined with the use of microsatellite markers. Heritability estimates were conducted by using the lisrel 8 program; a sib-pair analysis was conducted by using the sibpal program. Linear regression analyses were carried out between identical-by-descent status and squared within-pair differences of TC, LDL-C, HDL-C, and TG values. Heritability estimates of the lipid serum concentrations ranged from .58 to .66. A significant linkage relationship was found for HDL-C (P = .008) and TGs (P = .05) with D8S261 on chromosome 8p. However, no linkage was found between any of the lipid variables and the lipoprotein lipase gene locus (LPL GZ14/15 and D8S282). Because D8S261 is located approximately halfway between the LPL and macrophage scavenger receptor genes, we examined the nearby markers D8S549 and D8S1731. Linkage was found for HDL-C and D8S549 (P = .001) and for HDL-C and D8S1731 (P = .04). On the other hand, we found no linkage between the LDL receptor gene locus and LDL-C serum concentrations nor between the LPL gene locus and the various other lipid fractions. Our data suggest a significant influence of the macrophage scavenger receptor gene locus on HDL-C and weak influence on TG levels. We suggest that inherited variability in the macrophage scavenger receptor gene has an influence on serum lipid concentrations.