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.

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.

Angiotensin-converting enzyme and angiotensinogen gene polymorphisms, plasma levels, cardiac dimensions. A twin study.

We tested the hypotheses that angiotensin-converting enzyme insertion/deletion (I/D) and angiotensinogen 235 methionine/threonine (M/T) substitution gene polymorphisms influence angiotensin-converting enzyme and angiotensiongen serum concentrations and cardiac dimensions in 91 monozygotic and 41 dizygotic twin pairs. Cardiac dimensions were determined echocardiographically. Angiotensin-converting enzyme levels were 24 +/- 11, 43 +/- 18, and 58 +/- 24 U/L for the II, ID, and DD genotypes, respectively (P < .01). Posterior wall thickness was 8.1 +/- 1.3, 8.6 +/- 1.7, and 8.9 +/- 1.9 mm for these genotypes (P < .05). Angiotensin-converting enzyme levels were correlated with posterior wall thickness (r = .15, P < .05). The intrapair differences in angiotensin converting enzyme levels for monozygotic, concordant dizygotic, and discordant dizygotic twins were 1.36 +/- 1.6, 1.86 +/- 1.6, and 17.25 +/- 4.3 U/L, respectively. The angiotensinogen M/T genotypes exerted no influence on cardiac dimensions or on angiotensinogen concentrations. The additive genetic effect on angiotensin-converting enzyme levels (0.49), on posterior wall thickness (0.26), and on septum thickness (0.37) was significant (P < .01), although shared and nonshared environmental effects were also identified. Our data confirm the impressive effect that the angiotensin-converting enzyme D allele exerts on angiotensin-converting enzyme plasma levels. Furthermore, our data also suggest that the angiotensin-converting enzyme gene locus is primarily responsible for angiotensin-converting enzyme plasma levels. Our twin study also indicates that the angiotensin-converting enzyme gene locus is genetically linked to posterior wall thickness. The correlation between angiotensin-converting enzyme levels and posterior wall thickness suggests that this effect is exerted by angiotensin-converting enzyme. We were unable to demonstrate genetic linkage between the angiotensinogen gene locus and cardiac dimensions in this study.

Genetic influences on blood pressure with the cold-pressor test: a twin study.

OBJECTIVES: To determine the genetic and environmental contributions to resting blood pressure, the level of blood pressure during the cold-pressor test and the increase in blood pressure with the cold-pressor test in an adult cohort of normotensive twins. DESIGN AND METHODS: Ninety-one monozygotic and 41 dizygotic normal twin pairs were recruited by advertisement. The mean age was 34 +/- 14 years (mean +/- SD). Systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate were measured continuously at the finger (using a Finapres device) and verified at the upper arm oscillometrically (using a Dinamap device) every minute. The cold-pressor test was conducted by immersing the non-dominant hand into cold (< 4 degrees C) water for 2 min. Statistical analysis was performed by using the SPSS program; parameters of the quantitative genetic models were estimated by path-analysis techniques using the LISREL 8 program. RESULTS: Heritability estimates of additive genetic effects were statistically significant for SBP and DBP but not for heart rate during rest and during the cold-pressor test. Furthermore, the path analysis indicated shared as well as specific genetic components both for the blood pressure level at rest and for that during the cold-pressor test. However, the genetic influences on the blood pressure level at rest and on the increase in blood pressure during the cold-pressor test (the blood pressure level during the cold-pressor test minus that during rest) were entirely independent of one another. CONCLUSIONS: A significant genetic covariation exists for SBP and DBP during rest and during the cold-pressor test, as well as a significant genetic variation that is specific to the cold-pressor stress condition. These findings suggest that different genes or sets of genes contribute to blood pressure regulation during rest and to blood pressure reactivity to cold-pressor stress.

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.

Usefulness of piretanide plus ramipril for systemic hypertension: a multicenter trial.

To test the dose responses of piretanide, ramipril, and their combination in patients with essential hypertension, a prospective, randomized, double-blind, placebo-controlled trial was conducted in 480 patients. Twelve separate groups were studied: placebo, piretanide 3 mg, piretanide 6 mg, ramipril 2.5 mg, ramipril 5 mg, ramipril 10 mg, and their combinations, as single daily morning doses. Patients were randomized after a 2-week run-in period without drugs; treatment was given for 6 weeks. A dose response compared with placebo was found for both drugs; the combination was more effective than either drug alone. Piretanide 6 mg, combined with ramipril 5 mg, provided optimal blood pressure reduction. Self-reported adverse effects of both drugs and their combinations did not exceed those reported for placebo. A surface analysis suggested that piretanide primarily reduced systolic blood pressure, whereas ramipril was more effective in reducing diastolic blood pressure. The data attest to a combined efficacy of piretanide and ramipril in decreasing arterial blood pressure.

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.

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.

Twin zygosity. Automated determination with microsatellites.

OBJECTIVE: Twin zygosity determinations can be performed with anthropologic, serologic and genetic markers; however, these methods are more than occasionally inefficient, often expensive and sometimes inaccurate. We used microsatellites as DNA markers and developed a largely automated, rapid and efficient method of determining zygosity. STUDY DESIGN: We used five highly polymorphic short tandem repeat loci, coamplified by polymerase chain reaction (PCR) using fluorescence-labeled primers. Thirty-six samples were simultaneously analyzed by electrophoresis and laser detection. The PCR products were sized by automated fragment analysis. RESULTS: We typed 132 pairs of monozygotic (MZ) and dizygotic (DZ) twins. With five markers, the probability that any twin pair was MZ if all markers were concordant was 99%. CONCLUSION: This method is a rapid and reliable approach to zygosity detection.

[Thin layer analysis of talinolol (Cordanum) in urine--a screening method for monitoring of drug compliance in hypertensive patients]. / DC-Nachweis von Talinolol (Cordanum) im Urin--eine Screeningmethode zur Kontrolle des Einnahmeverhaltens bei Hypertonikern.

A simple and rapid analytical method for TLC detection of talinolol (Cordanum) is described. Because of its low technical expense it can be used for routine application in clinical laboratories. Triamteren (substance of contents of Triampur comp.) is detected simultaneously. This method has till now been applied to urine specimens of 145 hypertensive patients taking talinolol (n = 95) and triamteren (n = 50). The spectrofluorimetric analysis of talinolol was used as a reference method (r = 0.95).

[Comparative pharmacokinetic studies on the relative biologic availability of two propranolol preparations in patients with steady state essential hypertension]. / Vergleichende pharmakokinetische Untersuchungen zur relativen Bioverfügbarkeit von zwei Propranolol-Präparaten bei Patienten mit essentieller Hypertonie im steady-state.

Plasma propranolol concentrations were analyzed after Obsidan (VEB Isis-Chemie, Zwickau, GDR) (= preparation A) and another propranolol-preparation (= preparation B) in 10 patients with arterial hypertension of clinical stage I-II in a cross-over design. The concentration-time-curves (AUC0----infinity) were investigated up to 24 h after the oral intake of 40 mg of both preparations of propranolol and were nearly identical. In comparison with preparation B the relative bioavailability F was 104% for preparation A. The steady-state plasma concentrations of propranolol were within the therapeutic range of 50-100 ng/ml. They showed only interindividual variations about the factor 2-3. Peak plasma concentrations were observed 1,5-2 h after the oral application. There were no statistical differences in the pharmacokinetic parameters between the both preparations. The rate of elimination constants of 0,065 to 0,073 h-1 after preparation A and B explain the long duration of the therapeutic efficacy during chronic treatment.

[Comparative study of the relative bioavailabilities of two prazosin preparations in patients with essential hypertension]. / Vergleichende Untersuchungen zur relativen Bioverfügbarkeit von zwei Prazosinpräparaten bei Patienten mit essentieller Hypertonie.

The relative bioavailability of two different Prazosine preparations (Adversuten, VEB Arzneimittelwerk Dresden, GDR and Minipress, Pfizer GmbH, Karlsruhe, FRG) has been determined in 10 patients suffering from an essential hypertension by the cross-over test following a single oral application. The plasma concentrations determined on the same conditions revealed with both the preparations an almost equal blood level course. The pharmacokinetic parameters had been determined to the one-compartment system, demonstrating not any significant differences. Compared to the Minipress, the relative bioavailability of the preparation Adversuten was calculated to 102%. The discussion enters into a possible influence on the distribution parameters by alterations of the kidney function.

[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.

[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.

[Behavior of blood pressure in 3 shift work of workers with level I WHO hypertension]. / Blutdruckverhalten während der Dreischichtarbeit bei Werktätigen mit einer Hypertonie vom Schweregrad In. WHO.

Blood pressure tests were carried out on 40 shift workers with a hypertension level of 1 (according to WHO). Every 5 day period these tests were carried out before, during and after work in the early, late and night shifts. No significant change of both the systolic and the diastolic blood pressure could be found, which could result from shift work, before and after each shift irrespective of the blood pressure stabilization (good, satisfactory, unsatisfactory). The group containing satisfactorily as well as unsatisfactorily stabilized workers suffering from hypertension showed a significant decrease of the systolic blood pressure from the early shift through the late till the night shifts, with the diastolic blood pressure remaining constant. There were no apparent differences in the range of average blood pressure values regarding the various forms of treatment (without medication, monotherapy and combined therapy). The systolic blood pressure is significantly lower only in the group with no medication in the early shift after finishing work and it also decreases from the early shift through the late till the night shifts, while within the other therapy groups no change of both the systolic and the diastolic blood pressure was apparent. Thus shift work does not cause any measurable increase in blood pressure within the test group (suffering from hypertension) that would impair their working capacity. There is no increase of health risk with regard to the blood pressure response during shift work particularly during night work provided the blood pressure is within the normal range.