Results of the Ross operation in rheumatic versus non-rheumatic aortic valve disease.

BACKGROUND AND AIM OF THE STUDY: A total of 213 patients underwent the Ross operation at our institution between January 1990 and January 1999. Outcome was assessed in rheumatic (RH) patients and compared with that in patients with other etiology (non-RH). METHODS: After exclusion of 69 patients with a follow up of <18 months, the study group comprised 144 patients (119 RH, 25 non-RH). Patients were studied clinically and by echo-Doppler cardiography preoperatively, within 2 months and 6-8 months after surgery, and yearly afterwards. Preoperative assessment included age, gender, body surface area (BSA), type of aortic valve lesion and additional valve disease, left and right ventricular outflow tract (LVOT, RVOT) dimensions, and left ventricular (LV) size, function and mass. Postoperatively, patients were studied for presence and severity of autograft regurgitation, mitral regurgitation, LV size, function and mass, and incidence and timing of reoperation. RESULTS: On average, RH patients were older and had higher BSA, more aortic regurgitation than stenosis, more additional mitral valve disease (mostly regurgitation), larger LV size and poorer LV function. Mitral valve repair was performed in 24% of RH patients versus 0% of non-RH patients. Postoperatively, differences in LV size, function and mass remained present, but diminished during follow up. The autograft reoperation incidence was 22% (26/119) in RH patients versus 8% (2/25) in non-RH patients (p = NS). Preoperative predictors for reoperation in the RH group were severe concomitant mitral regurgitation (MR), followed by male gender and large indexed LVOT (all p<0.001 by discriminant analysis). CONCLUSION: Marked differences were present in patient characteristics between rheumatic and nonrheumatic patients who underwent the Ross operation. Rheumatic patients had a higher incidence of autograft reoperation. Severe concomitant MR was the most important predictor for reoperation in rheumatic patients.

Aneurysms complicating pulmonary autograft procedure for aortic valve replacement.

Aneurysm formation in the left ventricular outflow tract related to the proximal end of the pulmonary autograft after the Ross procedure was present in 2 patients. Both occurred late after operation and were associated with prolapse of a leaflet of the autograft and significant regurgitation. Both were repaired with no immediate complications. There was no evidence of infection at time of operation. The probable mechanisms underlying this complication and the possibilities of avoiding it are discussed.

Autograft failure after the Ross operation in a rheumatic population: pre- and postoperative echocardiographic observations.

BACKGROUND AND AIMS OF THE STUDY: Between January 1990 and July 1995, 108 patients underwent the Ross operation at our hospital. Most patients (90%) had severe aortic regurgitation (AR) in the setting of rheumatic heart disease. Although there have been no perioperative or late cardiac deaths, 12 patients (11%) developed severe AR requiring reoperation. MATERIAL AND METHODS: We performed an extensive and mostly retrospective analysis of echocardiographic data on all patients. Preoperative data were analyzed for age, sex, body surface area (BSA), size and comparison of the left and right ventricular outflow tracts (LVOT, RVOT), left ventricular (LV) size and function, and the presence of pulmonary regurgitation (PR) and concomitant mitral regurgitation (MR). Follow up data were analyzed for the presence, time of onset, evolution and severity of AR, characteristics of the AR jet, anatomic and functional aspects of the aortic root and valve, and evolution of LVOT diameter and LV size and function. RESULTS: Patients with autograft failure were younger with smaller BSA, larger indexed size of LVOT, RVOT and LV, and significantly more had concomitant severe MR. Postoperatively they had larger and increasing LVOT size. Trivial or mild AR was common and seen in almost all patients, as was a minimal degree of preoperative PR. Severe AR developed mostly after the first year of follow up, and reoperation was performed within three years in 11/12 patients. In nine patients cusp dilatation and prolapse (most frequently of the posterior cusp) was the cause of the AR, and rheumatic activity in three. Reoperation was not associated with mortality. CONCLUSION: In our population autograft failure seems to be related to age, BSA and (indexed) LVOT, RVOT and LV size, but only the presence of significant concomitant mitral regurgitation before surgery was identified as a predictor for reoperation. Prolapse of one or more cusps were the cause of the AR in most patients. The graft is sensitive for recurrent rheumatic activity.

Severely impaired fetal growth is preceded by maternal hemodynamic maladaptation in very early pregnancy.

OBJECTIVE: To test the hypothesis that in pregnancies complicated by intrauterine growth retardation (IUGR) maternal cardiovascular adaptation is already abnormal in the first weeks of pregnancy. SETTING: University Hospital Maastricht, Maastricht, The Netherlands. SUBJECTS: Fourteen healthy pregnant women, recruited from the subfertility clinic. Ten pregnancies were uneventful and four pregnancies resulted in the birth of growth retarded infants. METHODS: Maternal cardiovascular status was followed longitudinally by combined M-mode and Doppler echocardiography. Studies were performed weekly between the fifth and 10th week, at 14, 25 and 35 weeks and postpartum. Differences between the two groups were analyzed by nonparametric tests. RESULTS: In early pregnancy, the IUGR group differed from the normal group by a consistently smaller left atrial diameter and a cardiac output that failed to increase. Postpartum the subjects in the IUGR group had a significantly smaller left atrial diameter and faster mean circumferential fiber shortening. CONCLUSION: Maternal hemodynamic adaptation in the first weeks of pregnancy is defective in IUGR pregnancies, presumably associated with a concomitant inadequacy of the vascular filling state.

Maternal volume homeostasis in early pregnancy in relation to fetal growth restriction.

OBJECTIVE: To test the hypothesis that volume adaptation in pregnancies complicated by fetal growth restriction (FGR) is already abnormal very early in pregnancy. METHODS: In six pregnancies later complicated by FGR, volume homeostasis in the first 8 weeks was compared to that in ten normal pregnancies. Creatinine clearance, volume-dependent hormones, hemodilution-related variables, and ultrasonic cardiovascular dimensions were measured weekly between weeks 5 and 10, in the second and third trimesters, and postpartum. Differences between the two groups were analyzed by nonparametric tests. RESULTS: Very early in pregnancy, pregnancies complicated by FGR differed from normal pregnancies in the following ways: smaller left atrial diameter, smaller collapsible part of the inferior vena cava, lower serum sodium concentration, and smaller fall in serum creatinine and urea. CONCLUSION: Fetal growth restriction is preceded by defective volume adaptation very early in pregnancy. It appears that the maternal compensation mechanisms are unable to resolve the transient state of vascular underfill seen in this period in normal gestation.

Cross sectional Doppler echocardiography as the initial technique for the diagnosis of acute pulmonary embolism.

OBJECTIVE: To determine the value of cross sectional Doppler echocardiography and derived indices of right ventricular pressure and function in the initial diagnosis of pulmonary embolism. BACKGROUND: Most deaths from acute pulmonary embolism occur because of a delay in diagnosis. Ventilation-perfusion scans are not sufficiently sensitive, whereas angiography is invasive and associated with complications. The use of cross sectional Doppler echocardiography to assess acute changes in right ventricular filling pressure and function, and in pulmonary arterial systolic pressure and its relation to embolism has not been studied in a large population. METHODS: 60 consecutive patients with acute symptoms or haemodynamic instability suggestive of pulmonary embolism were studied. Confirmatory investigations included a ventilation-perfusion scan (36 patients), angiography (18 patients), surgery (5 patients), or necropsy (5 patients). RESULTS: There was evidence of right ventricular pressure or volume overload in all. This took the form of increased right ventricular end diastolic diameter and leftward bulging of the interventricular septum in diastole (56 patients); tricuspid valve regurgitation (56 patients) with the peak velocity of the regurgitant jet > 2.6 m/s; and a low collapse index for the inferior vena cava of < 40%, indicating raised mean right atrial pressure (in 49 patients). Intracardiac or pulmonary thrombi were visualised in 10 patients. In 14 patients treatment was undertaken on the basis of the echocardiographic signs alone. Four of them (with visible thrombi) recovered: the other 10 died. Lung emboli were demonstrated in 4 of 5 patients in whom necropsy was performed. CONCLUSIONS: Cross sectional Doppler echocardiography is a sensitive technique for the rapid identification of right ventricular overload in acute pulmonary embolism. It enables further investigations on treatment to be appropriately directed without delay. Resolution of emboli can also be assessed by serial measurement of the described indices.

Value of exercise Doppler-echocardiography in patients with mitral stenosis.

The value of exercise Doppler-echocardiography was studied in 60 patients with mitral valve stenosis. Patients were divided in three groups. In patients with a mitral valve area of more than 1.4 cm2, maximal and mean diastolic gradient over the mitral valve increased from 13.2 +/- 3.6 to 18.4 +/- 5.4 and from 5.2 +/- 1.9 to 8.8 +/- 3.0 mmHg, respectively. In patients with a mitral valve area in between 1.0 and 1.4 cm2, maximal and mean gradient increased from 19.0 +/- 8.0 to 28.1 +/- 8.9 and from 8.8 +/- 4.9 to 14.8 +/- 6.4 mmHg, respectively. In patients with a mitral valve area of less than 1 cm2, the maximal gradient increased from 21.5 +/- 5.8 to 34.2 +/- 8.7 and mean gradient increased from 11.8 +/- 4.1 to 20.3 +/- 5.8 mmHg. Mean tricuspid regurgitation velocity increased from 2.9 +/- 0.5 m/s to 3.6 +/- 0.5 m/s, indicating increase in right ventricular to right atrial pressure difference from 34 mmHg to 52 mmHg. We conclude that exercise during the Doppler-echocardiographic evaluation provides additional information about the hemodynamic significance of mitral stenosis and can therefore be of value in decision making.

Safety of radiofrequency catheter ablation of accessory atrioventricular pathways.

The acute anatomic and valvular consequences of radiofrequency catheter ablation of accessory pathways were evaluated in 62 patients by means of serial echocardiographic examinations. Semiquantitative assessment of valvular incompetence and classification into one of four grades according to the width and the extension of the jet from the valvular orifice were carried out. Segmental wall motion abnormalities were evaluated semiquantitatively with four grades of severity (normal, hypokinesia, akinesia, or dyskinesia). New echocardiographic abnormalities were observed in five patients. One thrombus on the ventricular aspect of the mitral valve, three hemodynamically insignificant pericardial effusions, and one increase in severity of tricuspid incompetence were found 1 day after radiofrequency catheter ablation. We conclude that echocardiographic changes after radiofrequency ablation of accessory pathways are rare and of minor significance. These findings confirm the safety of the procedure.

Early pregnancy changes in hemodynamics and volume homeostasis are consecutive adjustments triggered by a primary fall in systemic vascular tone.

OBJECTIVE: The purpose of this study was to test the hypothesis that early pregnancy changes in volume homeostasis develop as a consequence of preceding changes in maternal hemodynamics. STUDY DESIGN: Maternal cardiovascular function of 10 pregnant women was followed up by Doppler echocardiography. Vascular filling state and volume homeostasis were evaluated by echocardiographic index values, glomerular filtration rate, serum osmolality, and volume-regulating hormones. Studies were performed weekly in early pregnancy, in the second and third trimesters, and post partum. Changes relative to the fifth week and the consistency of changes between weeks 5 and 8 were evaluated by nonparametric statistics. RESULTS: In early pregnancy cardiac output increased and afterload decreased. Concomitant increases in ultrasonic preload index values and glomerular filtration rate were accompanied by decreases in serum renin, Na+, and osmolality. CONCLUSION: These data support the concept that maternal hemodynamic adaptation to pregnancy is most likely triggered by a primary fall in systemic vascular tone. The resulting rapid fall in preload and afterload leads to a compensatory increase in heart rate and activation of the volume-restoring mechanisms. Subsequently cardiac output increases because of a rise in stroke volume, which develops because the vascular filling state normalizes, whereas the reduced afterload reduction is maintained.

Risk of aortic dissection after aortic valve replacement.

Little information is available regarding the incidence of aortic dissection after previous aortic valve replacement (AVR), and factors associated with its development. Therefore, a meta-analysis of the literature was performed, and a patient population was studied retrospectively. Data from published studies showed that 87% of 31 patients were men (mean age 60 years), and 68% were known to have systemic hypertension. A dilated ascending aorta was observed at the time of AVR in 88% of patients. AVR was performed because of pure aortic regurgitation in 55% of patients, and combined aortic stenosis and regurgitation in 23%. More than 50% of patients did not survive dissection. The present series consisted of 7 patients. Four patients were known to the department before dissection occurred, and the other 3 were referred by other hospitals. Eighteen of 330 patients with previous AVR whose data were stored in an echocardiographic data base had an ascending aortic diameter > 50 mm. Of these 18 patients, aortic dissection occurred in 4. Three of the remaining 14 patients underwent elective ascending aortic replacement. Characteristics including sex, age, severity of dilatation, presence of progression in diameter, left ventricular function and time interval after AVR were not helpful in determining a cumulative risk for developing dissection. Because dissection occurred in 4 of 18 patients (22%) with an ascending aorta diameter > 50 mm, it is suggested to consider replacement of the ascending aorta during AVR when a value of 50 mm is exceeded.

A field trial among leprosy patients in Nigeria with depot injections of dapsone and monoacetyldapsone.

In two field trials in Nigeria, 74 male and female leprosy outpatients received intra-adipose depot injections of either dapsone (DDS) or monoacetyldapsone (MADDS) at 4-week intervals. Blood samples were taken regularly and sent to Amsterdam to determine the DDS and MADDS concentrations in serum using high-pressure liquid chromatography (HPLC). The DDS injection yielded a good sustained drug release. After repeated administration accumulation occurred, demonstrated by a statistically significant increase in the area under the curve (AUC) in time: until 28 days after the first injection, the mean AUC (+/- S.D.) amounted to 19.3 +/- 5.6 mg d/l in males and 15.1 +/- 5.2 in females; after the fourth injection, 26.4 +/- 7.5 and 24.6 +/- 9.0 mg d/l, respectively (p less than 0.001). One male patient developed an abscess at the injection site; otherwise no side effects were observed. Even better sustained-release results were observed with the MADDS injection. Unfortunately, the injection caused a number of abscesses. Consequently, the DDS injection was very well received by the patients of the DDS study, while half of the patients in the MADDS study would prefer tablets to the MADDS injection. Further investigations are required to find the cause of the abscesses before one of the injections, or possibly a combination of both, could be implemented in the multi-drug treatment regimen proposed by WHO to provide a valuable tool to combat noncompliance among leprosy patients.

Influence of once-monthly rifampicin and daily clofazimine on the pharmacokinetics of dapsone in leprosy patients in Nigeria.

In leprosy patients in Nigeria the influence of daily clofazimine and of once-monthly rifampicin on the pharmacokinetics of dapsone has been investigated. Three days after rifampicin the elimination half-life of dapsone was reduced from 40.4 to 25.3 h (n = 23). Correspondingly, the plasma dapsone 24 h after the last dose had fallen significantly from 2.63 to 2.02 mg/l. Clofazimine did not cause change in the pharmacokinetics of dapsone. It was concluded that, although rifampicin had a considerable influence on the pharmacokinetics of dapsone, there is no reason to adjust the dose of dapsone during multidrug therapy of leprosy.

Influence of once-monthly rifampicin and daily clofazimine on the pharmacokinetics of dapsone in leprosy patients in Nigeria

In leprosy patients in Nigeria the influence of daily clofazimine and of once-monthly rifampicin on the pharmacokinetics of dapsone has been investigated. Three days after rifampicin the elimination half-life of dapsone was reduced from 40.4 to 25.3 h (n = 23). Correspondingly, the plasma dapsone 24 h after the last dose had fallen significantly from 2.63 to 2.02 mg/l. Clofazimine did not cause change in the pharmacokinetics of dapsone. It was concluded that, although rifampicin had a considerable influence on the pharmacokinetics of dapsone, there is no reason to adjust the dose of dapsone during multidrug therapy of leprosy.

The absolute oral bioavailability of dapsone in dogs and humans.

The absolute oral bioavailability of dapsone (DDS) was established in dogs and healthy volunteers by comparing AUC's after oral and intravenous administration. Five female inbred beagles each received 100 mg DDS orally and intravenously as a bolus injection in a randomized cross-over study. DDS serum concentrations were determined using HPLC. After both routes of administration, linear pharmacokinetics were observed, the elimination half-life (t1/2) amounting between 5.8 and 10.2 h. After oral administration, AUC values between 56.1 and 99.2 mg X h X l-1 were found, while after intravenous administration AUC's were between 63.5 and 98.1 mg X h X l-1. The absolute oral bioavailability, corrected for differences in t1/2, averaged 107 +/- 9% (SD). A similar study was carried out in 2 female and 3 male healthy volunteers. The intravenous dose was reduced to 50 mg and given as an infusion. Pharmacokinetics were linear after both routes of administration. The t1/2 values amounted between 15.6 and 30.4 h. AUC's ranged from 24.0 to 75.4 mg X h X l-1 after oral administration and from 13.3 to 37.5 mg X h X l-1 after intravenous infusion of half of the oral dose. The absolute, t1/2-corrected oral bioavailability was calculated to be 86 to 104%. Complete bioavailability of DDS was demonstrated in dogs and healthy volunteers. The method used in this study might help to detect possible DDS malabsorption in leprosy and dermatitis herpetiformis patients.

Intra-adipose administration of monoacetyldapsone to healthy volunteers.

The pharmacokinetics of intra-adiposely administered monoacetyldapsone (particle size less than 20 micron) were investigated in 11 male and 11 female healthy volunteers. Dapsone and monoacetyldapsone concentrations in serum were determined by high-pressure liquid chromatography (HPLC). Injection of 1175 mg monoacetyldapsone, which is equivalent to 1000 mg dapsone, resulted in dapsone concentration/time profiles in all the volunteers characterized by peak concentrations ranging from 0.14 to 0.85 mg/l, and by averaged dapsone concentrations after 28, 42, and 56 days of 0.33, 0.19, and 0.10 mg/l, respectively. Areas under the curves ranged from 6.7 to 25.3 mg X day/l. Detectable concentrations (greater than 6 ng/ml) of dapsone were achieved for 56 days in most of the subjects. An estimation of the mean concentration after repeated injection every 4 weeks ranged from 0.24 to 0.90 mg/l. No differences in dapsone concentration/time course were detectable between men and women or between rapid and slow acetylators. The injection was generally well tolerated by the subjects. This, combined with the excellent sustained release properties, makes it a promising injection. In the future, it might contribute to combat noncompliance among leprosy patients, which is believed to be one of the main causes of dapsone resistance.

The pharmacokinetics of dapsone after oral administration to healthy volunteers.

After oral administration of 100 mg dapsone (DDS) to 25 healthy volunteers peak serum DDS concentrations between 1.10 and 2.33 mg l-1 were reached within 0.5 to 4 h. AUCs varied from 20.3 to 75.4 mg l-1 h, while the elimination half-lives ranged from 11.5 to 29.2 h. The apparent volumes of distribution were 0.84 to 1.26 l kg-1 body weight, assuming complete bioavailability. Statistically significant differences in peak drug concentration, peak time and AUC existed between males and females. Absorption and elimination of DDS appeared to be faster than reported in other studies, suggesting differences in DDS kinetics between healthy volunteers and patients.

Sustained release properties of an intra-adiposely administered dapsone depot injection.

A dapsone depot injection, consisting of dapsone crystals of bipyramidal shape with a particle size of 38 micron-63 micron suspended in an aqueous vehicle, appeared to result in different concentration/time profiles in men and women when delivered "intramuscularly." This phenomenon can be explained by the larger skin-to-muscle distance in women than in men. Injections intended to be delivered intramuscularly are, in fact, administered into subcutaneous fatty tissue in most of the women. Because sustained release properties were more satisfactory in women than in men, in this study the absorption of dapsone was investigated after administration of the same injection into gluteal fatty tissue. Via this route of administration, for which the term intra-adipose is used, 12 female and 15 male healthy volunteers received 1000 mg dapsone, after which blood samples were taken at regular intervals for 35 days to determine dapsone and monoacetyldapsone concentrations in serum using high-pressure liquid chromatography with fluorometric detection. No important differences between men and women appeared to exist at any time point after injection. The peak concentrations were 0.69 +/- 0.40 mg/l in men and 0.84 +/- 0.31 mg/l in women. No important side effects were observed, either locally or systemically. Volunteers who previously received an intramuscular injection preferred the intra-adipose administration. The good depot properties and better acceptance of intra-adipose dapsone administration are reasons to prefer this route of administration.