Pharmacokinetic parameters of tibolone and metabolites in plasma, urine, feces, and bile from ovariectomized cynomolgus monkeys after a single dose or multiple doses of tibolone.

Levels of nonsulfated and sulfated tibolone metabolites were determined in plasma, urine, and feces from six ovariectomized, mature female cynomolgus monkeys after a single dose and multiple p.o. doses (including bile) of tibolone using validated gas chromatography/mass spectrometry and liquid chromatography/tandem mass spectrometry assays. In plasma, the predominant nonsulfated metabolite after single and multiple dosing was the estrogenic 3alpha-hydroxytibolone; levels of the estrogenic 3beta-hydroxytibolone were 10-fold lower and of progestagenic/androgenic Delta(4)-tibolone, 5-fold lower. Tibolone was undetectable. The predominant sulfated metabolite was 3alphaS,17betaS-tibolone; levels of 3betaS,17betaS-tibolone were about 2-fold lower, and monosulfated 3-hydroxymetabolites were about 10-fold lower. After multiple doses, areas under the curve of nonsulfated metabolites were lower (2-fold), and those of sulfated metabolites were 25% higher. In plasma, >95% metabolites were disulfated. In urine, levels of all the metabolites after single and multiple doses were low. After a single dose, high levels of 3beta-hydroxytibolone and the 3-monosulfated metabolites (3betaS,17betaOH-tibolone and 3alphaS,17betaOH-tibolone) were found in feces. After multiple dosing, 3alpha-hydroxytibolone increased, and the ratio of 3alpha/3beta-hydroxytibolone became about 1. The predominant sulfated metabolite was 3alphaS,17betaS-tibolone. Levels of all the metabolites in feces were higher after multiple doses than after a single dose. Levels of nonsulfated and 3-monosulfated metabolites were higher in feces than in plasma. Bile contained very high metabolite levels, except monosulfates. This may contribute to the metabolite content of the feces after multiple doses. 3beta-Hydroxytibolone and 3alphaS,17betaS-tibolone predominated. In conclusion, tibolone had different metabolite patterns in plasma, urine, feces, and bile in monkeys. The bile contributed to the metabolite pattern in feces after multiple doses. The major excretion route was in feces.

Selective tissue distribution of tibolone metabolites in mature ovariectomized female cynomolgus monkeys after multiple doses of tibolone.

Tibolone is a selective tissue estrogenic activity regulator (STEAR). In postmenopausal women, it acts as an estrogen on brain, vagina, and bone, but not on endometrium and breast. Despite ample supporting in vitro data for tissue-selective actions, confirmative tissue levels of tibolone metabolites are not available. Therefore, we analyzed tibolone and metabolites in plasma and tissues from six ovariectomized cynomolgus monkeys that received tibolone (0.5 mg/kg/day by gavage) for 36 days and were necropsied at 1, 1.25, 2.25, 4, 6, and 24 h after the final dose. The plasma and tissue levels of active, nonsulfated (tibolone, 3alpha-hydroxytibolone, 3beta-hydroxytibolone, and Delta(4)-tibolone), monosulfated (3alpha-sulfate,17beta-hydroxytibolone and 3beta-sulfate,17beta-hydroxytibolone), and disulfated (3alpha,17beta-disulfated-tibolone and 3beta,17betaS-disulfated-tibolone) metabolites were measured by validated gas chromatography with mass spectrometry and liquid chromatography with tandem mass spectrometry. Detection limits were 0.1 to 0.5 ng/ml (plasma) and 0.5 to 2 ng/g (tissues). In brain tissues, estrogenic 3alpha-hydroxytibolone was predominant with 3 to 8 times higher levels than in plasma; levels of sulfated metabolites were low. In vaginal tissues, major nonsulfated metabolites were 3alpha-hydroxytibolone and the androgenic/progestagenic Delta(4)-tibolone; disulfated metabolites were predominant. Remarkably high levels of monosulfated metabolites were found in the proximal vagina. In endometrium, myometrium, and mammary glands, levels of 3-hydroxymetabolites were low and those of sulfated metabolites were high (about 98% disulfated). Delta(4)-Tibolone/3-hydroxytibolone ratios were 2 to 3 in endometrium, about equal in breast and proximal vagina, and 0.1 in plasma and brain. It is concluded that tibolone metabolites show a unique tissue-specific distribution pattern explaining the tissue effects in monkeys and the clinical effects in postmenopausal women.

Pharmacokinetic parameters of sulfated tibolone metabolites in postmenopausal women after single and multiple doses of tibolone.

The objective of this study was to determine pharmacokinetic parameters of sulfated tibolone metabolites after single dose and their accumulation after multiple doses of tibolone. Blood samples from postmenopausal women in a single-dose (2.5 mg tibolone), open-label study (n=8) and multiple-dose (placebo, 0.3, 0.625, 1.25, or 2.5 mg/day tibolone for twenty-six cycles of 28 days), randomized, double-blind study (n=15) were analyzed for non-sulfated and sulfated tibolone metabolites by validated gas chromatography-mass spectrometry (GC-MS) and liquid chromatography with tanolam mass spectrometry (LC-MS/MS), respectively. The predominant non-sulfated and sulfated metabolites after a single dose were 3alpha-hydroxy-tibolone and 3alpha,17beta-di-sulfated (di-S)-tibolone. At 3 h, >90% of metabolites were sulfated. Tibolone and Delta(4)-tibolone were detectable for about 6 h. After multiple treatment cycles with different doses, metabolite levels at 10 h were dose-related and levels of di-S metabolites were three- to fivefold higher than after a single dose. Tibolone metabolite levels did not differ between cycles. Inactive di-S tibolone metabolites predominated in blood. No accumulation occurred between cycles 7 and 26.

Molecular analysis of human endometrium: short-term tibolone signaling differs significantly from estrogen and estrogen + progestagen signaling.

Tibolone, a tissue-selective compound with a combination of estrogenic, progestagenic, and androgenic properties, is used as an alternative for estrogen or estrogen plus progesterone hormone therapy for the treatment of symptoms associated with menopause and osteoporosis. The current study compares the endometrial gene expression profiles after short-term (21 days) treatment with tibolone to the profiles after treatment with estradiol-only (E(2)) and E(2) + medroxyprogesterone acetate (E(2) + MPA) in healthy postmenopausal women undergoing hysterectomy for endometrial prolapse. The impact of E(2) treatment on endometrial gene expression (799 genes) was much higher than the effect of tibolone (173 genes) or E(2) + MPA treatment (174 genes). Furthermore, endometrial gene expression profiles after tibolone treatment show a weak similarity to the profiles after E(2) treatment (overlap 72 genes) and even less profile similarity to E(2) + MPA treatment (overlap 17 genes). Interestingly, 95 tibolone-specific genes were identified. Translation of profile similarity into biological processes and pathways showed that ER-mediated downstream processes, such as cell cycle and cell proliferation, are not affected by E2 + MPA, slightly by tibolone, but are significantly affected by E(2). In conclusion, tibolone treatment results in a tibolone-specific gene expression profile in the human endometrium, which shares only limited resemblance to E(2) and even less resemblance to E2 + MPA induced profiles.

Metabolism of exogenous sex steroids and effect on brain functions with a focus on tibolone.

Around the menopause, changes in ovarian secretion of steroids result in changes in brain function: hot flushes and sweating later followed by changes in mood, libido and cognition. The relationship between sex steroids and brain functions are reviewed, with focus on hormonal treatments, in particular tibolone, on the postmenopausal brain and on associations between tissue levels and brain functions. Data on steroid levels in human brain are limited. Exogenous oestrogens alone or combined with progestagens reduce hot flushes and sweating, and may favourably affect anxiety, depression and mood. Testosterone alone or combined with E(2) improves libido and mood. Tibolone reduces hot flushes and sweating, and improves mood and libido, but does not stimulate endometrium or breast, like oestrogens. Tibolone is an ideal compound for studying steroid levels and metabolism in brain in view of its structural differences from endogenous steroids and its extensive metabolism required to express its endocrine effects. Brain levels of tibolone metabolites were measured in ovariectomized cynomolgus monkeys receiving tibolone for 36 days. Compared to serum, higher levels of the oestrogenic 3alpha/beta-hydroxytibolone and the androgenic/progestagenic Delta(4)-tibolone, and lower levels of sulphated metabolites are found in various brain regions. The high levels of oestrogenic metabolites in the hypothalamus explain hot flush reduction. Combined with the presence of Delta(4)-tibolone, the tibolone-induced increase in free testosterone through SHBG reduction explains androgenic effects of tibolone on mood and libido. The levels of tibolone metabolites in the monkey brain support tibolone's effects on brain functions.

Pharmacokinetics of tibolone in early and late postmenopausal women.

AIMS: Tibolone is a tissue-specific compound with favourable effects on bone, vagina, climacteric symptoms, mood and sexual well being in postmenopausal women, without stimulating the endometrium or breast. Since tibolone is used for the treatment of both young and elderly postmenopausal women, its pharmacokinetics were studied to investigate potential differences with age. In addition, the bioequivalence of the 1.25 and 2.5 mg tablets was evaluated. METHODS: Single doses of 1.25 or 2.5 mg of tibolone were given in a double-blind, randomized, two-way cross-over study to women aged between 45 and 55 years or between 65 and 75 years of age. RESULTS: Age did not have a significant effect on C(max), t(max), and t(1/2) of tibolone and its metabolites and on the body weight standardized oral clearance (CL/F kg(-1)) of the 3alpha- and 3beta-hydroxy tibolones. In early postmenopausal women, significantly lower values were found for the AUC(0,16 h), and AUC(0, infinity ) of 3alpha-hydroxy tibolone 24.6+/-6.6 vs 29.2+/-4.9 and 27.1+/-6.9 vs 32.3+/-6.5 ng ml(-1) h for the 1.25 mg tablet, respectively, and 45.4+/-13.9 vs 55.7+/-14.1 and 49.6+/-14.6 vs 62.6+/-17.3 ng ml-1 h for the 2.5 mg tablet, respectively. When these values were adjusted for the significantly higher body weight of the early postmenopausal women, the differences disappeared. No significant differences between early and late postmenopausal women were found for the AUC(0,8 h), and AUC(0, infinity) of 3beta-hydroxy tibolone. The rate of absorption of tibolone and the rates of absorption or formation of the 3alpha- and 3beta-hydroxy tibolones were significantly higher after the 1.25 mg dose than after the 2.5 mg tablet, resulting in increases of 32%, 27% and 17% for the dose normalized-C(max) of tibolone and the 3alpha- and 3beta-hydroxy tibolones, respectively. tmax for tibolone and its metabolites was 12-27% less after 1.25 mg compared to 2.5 mg, which was statistically significant. The two formulations were bioequivalent with respect to the dose-normalized AUC(0, infinity) and the AUC(0,t(fix)) values for the 3alpha-hydroxy tibolone (ratio point estimate [90%, confidence limits]: 1.08 [1.04, 1.14] and 1.08 [1.03, 1.13], respectively) and for the 3beta-hydroxy tibolone (1.07 [1.01, 1.14] and 1.04 [0.96, 1.12], respectively). Both formulations were also bioequivalent with respect to CL/F kg(-1) and t(1/2). CONCLUSIONS: The pharmacokinetics of tibolone are similar in early (age 45-55 years) and late (65-75 years) postmenopausal women. The 2.5 and 1.25 mg tablets are bioequivalent with respect to the extent of absorption. The rate of absorption or formation of the metabolites of tibolone were not bioequivalent, but these differences are considered to have no clinical relevance in view of the chronic administration of tibolone.

Tibolone and 5alpha-dihydrotestosterone alone or in combination with an antiandrogen in a rat breast tumour model.

Tibolone was combined with the antiandrogen flutamide to determine whether the inhibition of tumour growth in the prophylactic 7,12-dimethylbenz(a)anthracene (DMBA) rat model could be attributed to androgenic properties of one of its metabolites. The mean tumour load after tibolone (0.25 or 1.0 mg/kg twice daily orally for 10 weeks) was 125 and 255 versus 718 mm2 for placebo. The mean number of tumours were 1.2 and 2.0 versus 5.8, respectively. Combined with flutamide (10 mg/kg twice daily orally) both doses of tibolone did not result in an increase compared to placebo, but in significantly lower tumour loads (160 and 64 versus 718 mm2, respectively) and smaller numbers of tumours (0.8 and 1.0 versus 5.8, respectively). The differences between tibolone monotherapy and the combination groups with flutamide were not statistically significant indicating that flutamide did not reverse tibolone's inhibition of tumour growth. The positive control, 5alpha-dihydrotestosterone (DHT), entirely suppressed tumour development and flutamide abolished the inhibitory effect of DHT. Thus, unlike DHT, tibolone does not exert its beneficial effect in DMBA-induced tumours via the androgen receptor, but acts via different mechanisms.

Tibolone: a compound with tissue specific inhibitory effects on sulfatase.

The aim was to test whether sulfatase activity is differently regulated by tibolone in human bone, endometrium and breast cells since selective inhibition of sulfatases in various tissues may contribute to the tissue-specificity of tibolone. Tibolone, its 3 alpha- and 3 beta-hydroxy metabolites and their 3-sulfated forms, and its Delta(4)-isomer strongly (70-90%) inhibited the sulfatase activity in human breast cell lines (two T-47D clones) and intermediately (8-43%) in human endometrial cells (HEC-1A). In contrast, they did not inhibit sulfatase in two human osteoblast-like cell lines (MG 63, HOS TE-85). The specific sulfatase inhibitor, EMATE, showed inhibition in all cell lines. Just as estrone sulfate, 3 alpha-sulfated tibolone was also converted by sulfatase to the unconjugated 3 alpha-hydroxy-tibolone intracellularly in all cell lines. The tissue specific inhibition pattern of sulfatase activity by tibolone and its metabolites suggest that tibolone could be protective against development of mammary carcinomas, whereas it retains favorable estrogenic effects on bone.

Effects of estrogens and hormone replacement therapy on breast cancer risk and on efficacy of breast cancer therapies.

This review summarises preclinical and clinical data on effects of endogenous and exogenous estrogens on probability of breast cancer diagnosis, and on the course and efficacy of breast cancer therapies. The data indicate that higher endogenous estrogen exposure (e.g. pregnancy, early menarche and late menopause, estrogen levels in future breast cancer patients, obesity) or exogenous estrogens (oral contraceptives; hormone replacement therapies) may be associated with an increased probability of breast cancer diagnosis. However, there is little evidence that estrogens have deleterious effects on the course of breast cancer. Moreover, increased incidence of breast cancer diagnosis after prolonged hormone replacement therapy (HRT) use seems to be associated with clinically less advanced disease. In studies assessing both diagnosis and mortality, HRT is frequently associated with reduced mortality compared to never users. The interaction of progestagens and estrogens on the probability of breast cancer diagnosis is complex and dependent on type of progestagens and regimens employed. Efficacy of current treatment modalities for breast cancer (surgery, irradiation, adjuvant therapy or chemotherapy) is not negatively influenced by estrogens at concentrations considerably higher than those attained with current HRT preparations. Although it cannot be excluded that estrogens increase the probability of breast cancer diagnosis, available data fail to demonstrate that, once breast cancer has been diagnosed, estrogens worsen prognosis, accelerate the course of the disease, reduce survival or interfere with the management of breast cancer. It may therefore be concluded that the prevalent opinion that estrogens and estrogen treatment are deleterious for breast cancer, needs to be revisited. However, results of ongoing prospective, randomised clinical trials with different HRT regimens in healthy women or breast cancer survivors are needed to provide more definite conclusions about risks and benefits of HRT.

To operate or not on elderly patients with aortic stenosis: the decision and its consequences.

OBJECTIVE: To evaluate the application of guidelines in the decision making process leading to medical or surgical treatment for aortic stenosis in elderly patients. DESIGN: Cohort analysis based on a prospective inclusive registry. SETTING: 205 consecutive patients (>/= 70 years) with clinically relevant isolated aortic stenosis and without serious comorbidity, seen for the first time in the Doppler-echocardiographic laboratories of three university hospitals in the Netherlands. RESULTS: The initial choice was surgery in 94 patients and medical treatment in 111. Only 59% of the patients who should have had valve replacement according to the practice guidelines were actually offered surgical treatment. These were mainly symptomatic patients under 80 years of age with a high gradient. Operative mortality (30 days) was only 2%. The three year survival was 80% in the surgical group (17 deaths among 94 patients) and 49% in the medical group (43/111). Multivariate analysis showed that only patients with a high baseline risk, mainly determined by impaired left ventricular function, had a significantly better three year survival with surgical treatment than with medical treatment. CONCLUSIONS: In daily practice, elderly patients with clinically relevant symptomatic aortic stenosis are often denied surgical treatment. This study indicates that a surgical approach, especially where there is impaired systolic left ventricular function, is associated with better survival.

[Quality assessment indicators of cardiac surgeons' work; the validity of mortality rates]. / Rapportcijfers voor de hartchirurg; validiteit van waargenomen verschillen in sterfte.

OBJECTIVE: To determine the possibility of comparing the mortality rates of patients operated by different heart surgeons with each other. DESIGN: Retrospective cohort study. SETTING: Academic Medical Centre, Amsterdam, the Netherlands. PATIENTS AND METHODS: Clinical information, operation data and follow-up data on 783 patients who had undergone cardiac valve replacement, were collected from the clinical records. Aortic valve replacement had been performed in 446 patients (1979-1986) and mitral valve replacement in 337 patients (1980-1990). RESULTS: The one-year mortality rate was higher among patients operated on by heart surgeon A than among patients operated on by the other heart surgeons from the same team, viz. 16.4% and 9.5%, respectively, an absolute difference of 6.9%. The 95% confidence interval of the difference was 1.7-12.9. However, it was also found that the risk profiles of these patients of surgeon A differed from those of the other patients. After multivariate correction for this difference in risk profile, the difference in mortality was no longer statistically significant. CONCLUSION: The differences in mortality observed in our study could not be attributed to difference in quality of the heart surgeons, but were related with the risk profiles of the patients operated by one of them. Thorough analysis with correction for risks is necessary for the assessment of the quality of care, if the conclusions are not to be misleading.

Analysis of risk factors for excess mortality after aortic valve replacement.

OBJECTIVES: This study sought to identify risk factors for both late observed and late "excess" mortality after aortic valve replacement and to examine the causes of late mortality. BACKGROUND: Because operative mortality after aortic valve replacement is very low, the timing of surgical intervention should focus on maximizing long-term survival. However, to judge the effect of valve replacement on long-term survival in an elderly population, it is important to separate mortality resulting from extraneous causes (background mortality) from disease-related mortality (excess mortality). Background mortality can be estimated by calculating expected mortality on the basis of age and gender. METHODS: From 1966 to 1986, 643 patients (mean age 59.6 years, 138 [21%] > or = 70 years old) underwent aortic valve replacement, 129 of whom also underwent coronary bypass grafting; 594 patients survived > or = 30 days after the procedure. The overall operative mortality rate for isolated aortic valve replacement decreased over time from 25.5% (1966 to 1972) to 2.6% (1980 to 1986). Cumulative total follow-up after discharge was 3,603 patient-years. Multivariate analysis was performed for both observed and excess mortality. RESULTS: Risk factors for both observed and excess mortality were previous myocardial infarction, coronary artery disease, heart failure and atrial fibrillation. Although age > or = 70 years was a risk factor for observed mortality (hazard rate ratio [HRR] 2.4, 95% confidence interval [CI] 1.6 to 3.7), it was not a risk factor for excess mortality. In contrast, isolated aortic regurgitation was an important risk factor for excess mortality only (HRR 3.8, 95% CI 1.3 to 11.2). Late mortality was valve related in 22% of patients, including sudden death in 7% and cerebral vascular accidents in 7%. Congestive heart failure was an important cause of death (21%) irrespective of the time elapsed since aortic valve replacement. In patients with aortic regurgitation, congestive heart failure was the main cause of death (38%); in patients with aortic regurgitation and preoperative heart failure or severe left ventricular dysfunction, heart failure was the cause of death in 44% and 63%, respectively. CONCLUSIONS: Analysis of excess mortality revealed that older age in itself is not a risk factor for late mortality after aortic valve replacement. Aortic regurgitation carries a high risk, probably associated with left ventricular dysfunction at the time of operation. Earlier operation may be warranted in such patients.

Effects of ethinylestradiol on the course of spontaneous autoimmune disease in NZB/W and NOD mice.

Sex hormones affect (auto)immune responses in various ways. Investigations of the effects of estrogens have produced contradictory results. We studied the effects of gender, gonadectomy and of (supra)physiological doses of (the orally active) ethinylestradiol (EE) in two spontaneous autoimmune disease models: the NZB/NZW F1 and NOD mice. In both models we confirmed the female preponderance and the aggravating effects of gonadectomy in males but not in females. The accelerated mortality found in NZB/W mice treated with supraphysiological doses of EE was not associated with increased proteinuria, increased IgG-type anti-DNA levels or increased mononuclear cell infiltrations in the submandibular gland. In contrast, we found a severe reduction in body weight and in the weights of various organs (indications of toxicity), and a decrease rather than an increase in proteinuria and in mononuclear cell infiltrations (indications for autoimmunity). Physiological doses of EE did not significantly affect disease symptoms. In the NOD model a near-physiological, non-toxic dose of EE did not cause consistent changes on immunological disease symptoms either. Therefore, we conclude that the sexual dichotomy in spontaneous autoimmune models is due to protective effects of androgens and that the mortality by estrogens is due to toxic effects rather than accelerated autoimmunity.

Effects of changes in management of active infective endocarditis on outcome in a 25-year period.

The clinical outcome and long-term follow-up of 130 consecutive patients (141 episodes) with active infective endocarditis who were treated between 1966 and 1991 were analyzed. There was a shift toward a higher proportion of referred patients (39 to 78%), patients aged > 60 years (11 to 41%) and urgent surgical treatment (11 to 44%). Medical treatment was administered in 98 patients (70%); 30-day mortality was 27%. Surgery was performed in 43 patients (30%), with an operative mortality of 26%; 9 of 14 patients (64%) who underwent operation within the first week of admission died. Patients with severe heart failure are at the highest risk for early mortality (relative risk = 21.1; 95% confidence interval 7.4-60.3). Referred patients were much more often treated surgically than were nonreferred patients (48 versus 14%) and had a lower operative mortality (24 vs 30%). Nonreferred patients were more often treated medically (86 vs 52%) and with lower mortality (19 vs 39%). The total follow-up time was 730 patient-years; only 1 patient was considered lost to follow-up. The overall cumulative 5-year and 10-year survival after hospital discharge for patients after urgent surgery were 84 +/- 7% and 53 +/- 7%, respectively, and for those after medical treatment 84 +/- 5% and 77 +/- 6%, respectively. The probability of remaining free of late events (recurrent endocarditis, late valve replacement or death) during 5 and 10 years for patients after urgent surgery was 84 +/- 7% and 53 +/- 15%, respectively, and for those after medical treatment 59 +/- 6% and 40 +/- 7%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Background mortality in clinical survival studies.

In long-term follow-up studies of survival after an initial event (eg, an operation) mortality from causes other than the one under study obscures the results, especially in elderly patients. In the traditional approach to the calculation of expected mortality a fictitious cohort is drawn from the general population, being matched for age, sex, and calendar time at the time of the initial event. The membership of this cohort is then kept constant from the initial event until the closing date of the study. The survival and mortality of this static cohort is then compared with that of the dynamic patient cohort to throw light on mortality from extraneous causes. This method can lead to severe bias if there is a strong correlation between the duration of observation of the patients and their age. The analysis can be improved by applying rate adjustment when calculating the background component of mortality. In this approach mortality rates from the general population are adjusted (weighted) so that the age, sex, and calendar year are at all times identical with those of each of the patients still alive and under observation. This is illustrated by means of a simplified example and a real-life one from a study at survival after aortic valve replacement. Estimation of rate-adjusted background mortality provides a framework that may put long-term survival, especially of elderly patients, in proper perspective.

Aortic valve regurgitation and the congenitally bicuspid aortic valve: a clinico-pathological correlation.

OBJECTIVE: To investigate the morphology of congenitally bicuspid aortic valves causing pure valve regurgitation. DESIGN: A case series collected over five years. SETTING: An academic hospital. PATIENTS AND METHODS: One hundred and forty eight excised congenitally bicuspid aortic valves. The morphological findings were correlated with sex, age, clinical history, and data on haemodynamic function before operation. Pure valve regurgitation was defined as grade 3-4/4 with a gradient less than 30 mm Hg. Aortic root dilatation was evaluated angiographically or echocardiographically or both. RESULTS: Three types were recognised: valves that were purely bicuspid (23%), bicuspid valves with a raphe (34%), and valves with an additional indentation of the free edge of the conjoined cusp (43%). In 14 cases pure valve regurgitation was present. Dilatation of the aortic root was present in 47 cases. The relative risk for regurgitation when the aortic root was dilated (compared with no dilatation) was 3.99. The relative risk for valve regurgitation when there was indentation of the conjoined cusp (compared with no indentation) was 4.95. The mean age at operation in patients with pure regurgitation was 56 years, which is significantly younger (p = 0.0008) than that of patients with a congenitally bicuspid valve with combined valve stenosis and regurgitation (64.7 years). CONCLUSIONS: Congenitally bicuspid aortic valves with a central indentation of the free edge of the conjoined cusp seem particularly likely to develop pure aortic valve regurgitation.

Value of exercise Doppler echocardiography in patients with prosthetic or bioprosthetic cardiac valves.

Doppler echocardiographic evaluation of the prosthetic valve function is usually performed at rest, although this situation is not representative for patients' daily activities. Therefore, a symptom-limited Master 2-step test was performed in 61 asymptomatic patients with normal left ventricular function. No adequate Doppler signals were obtained in 5 of 61 patients (8%) within 60 second after termination of exercise. In patients with aortic valve prostheses (n = 24), heart rate increased from 74 +/- 10 to 105 +/- 18 beats/min, the maximal instantaneous gradient from 44 (range 22 to 90) to 68 (range 28 to 165) mm Hg (r = 0.89) and the mean gradient from 24 (range 12 to 50) to 39 (range 18 to 100) mm Hg (r = 0.90). In 6 of 11 patients with a maximal flow velocity ratio between the left ventricular outflow tract and the aortic valve prosthesis less than or equal to 0.25, the mean gradient increased to a value greater than or equal to 50 mm Hg after exercise, whereas in patients with a ratio of greater than or equal to 0.25, this never occurred. In patients with mitral valve prostheses (n = 39), heart rate increased from 80 +/- 12 to 116 +/- 14 beats/min and mean gradient from 6 (range 3 to 10) to 14 (range 6 to 25) mm Hg (r = 0.59). The correlation of the mean diastolic pressure gradient after exercise with pressure half-time was 0.66. Systolic pulmonary artery pressure at rest and after exercise could be determined in 22 of 39 patients (56%) and increased from 34 (range 20 to 70) to 57 (range 35 to 110) mm Hg. It is concluded that the response to exercise can, to a large extent, be inferred from Doppler parameters at rest, particularly in patients with aortic valve prostheses. The clinical implication of the high gradients found in some asymptomatic patients in the present study should be elucidated by follow-up studies.