Is the intrauterine device appropriate contraception for HIV-1-infected women?

OBJECTIVE: To assess whether the risk of complications is higher in HIV-1-infected women compared with non-infected women in the two years following insertion of the intrauterine contraceptive device. DESIGN: Prospective cohort study. POPULATION: Six hundred and forty-nine women (156 HIV-1-infected, 493 non-infected) in Nairobi, Kenya who requested an intrauterine contraceptive device and met local eligibility criteria. METHODS: We gathered information on complications related to the use of the intrauterine contraceptive device, including pelvic inflammatory disease, removals due to infection, pain or bleeding, expulsions, and pregnancies at one, four, and 24 months after insertion by study physicians masked to participants' HIV-1 status. Cox regression was used to estimate hazard ratios. RESULTS: Complications were identified in 94 of 636 women returning for follow up (14.7% of HIV-1-infected, 14.8% of non-infected). The incidence of pelvic inflammatory disease was rare in both infected (2.0%) and non-infected (0.4%) groups. Multivariate analyses suggested no association between HIV-1 infection and increased risk of overall complications (hazard ratio = 1.0; 95% CI 0.6-1.6). Infection-related complications (e.g. any pelvic tenderness, removal for infection or pain) were also similar between groups (10.7% of HIV-1-infected, 8.8% of non-infected; P = 0.50), although there was a non-significant increase in infection-related complications among HIV-1-infected women with use of the intrauterine contraceptive device longer than five months (hazard ratio = 1.8; 95% CI 0.8-4.4). Neither overall nor infection-related complications differed by CD4 (immune) status. CONCLUSIONS: HIV-1-infected women often have a critical need for safe and effective contraception. The intrauterine contraceptive device may be an appropriate contraceptive method for HIV-1-infected women with ongoing access to medical services.

Single and multiple exposure tolerance study of cellulose sulfate gel: a Phase I safety and colposcopy study.

Vaginally applied gels offer a promising approach for preventing unwanted pregnancies and sexually transmitted infections. Cellulose sulfate (CS) is a non-cytotoxic antifertility agent that also exhibits in vitro antimicrobial activity against sexually transmitted pathogens, including HIV. This was a randomized, double-blinded, Phase I study of 2.5 mL and 5.0 mL doses of 6% CS gel. A single vaginal application of the gel followed by five consecutive daily doses was assessed for genital irritation, safety, vaginal leakage, and product acceptability compared to two controls, Conceptrol, which is a marketed contraceptive gel containing nonoxynol-9, and K-Y jelly. The results suggest that the safety of 6% CS was comparable to that of Conceptrol and K-Y jelly, and it may be associated with less genital irritation. The 2.5 mL dose of CS may be preferable according to the participants' reports of leakage. All the products had similar acceptability profiles.

Long-term follow-up after quinacrine sterilization in Vietnam. Part I: interim efficacy analysis.

OBJECTIVE: To determine the long-term efficacy of nonsurgical sterilization with quinacrine. DESIGN: Observational cohort study. SETTING: Rural provinces in northern Vietnam. PATIENT(S): Two thousand seven hundred and nine women who had quinacrine insertions between 1989 and 1993. INTERVENTION(S): Interviews in 1994, 1995, and 1996 and review of available medical records. Pregnancy rates were corrected for problems in detecting and confirming pregnancies. MAIN OUTCOME MEASURE(S): Pregnancy rates. RESULT(S): Over 90% of women were interviewed at least once. Uncorrected cumulative pregnancy rates were 12.9% at 5 y after two insertions and 27.3% after one insertion. Effectiveness varied by age group: the partially corrected pregnancy rates after two insertions were 6.8% in women 35 or older at the time of insertion and 13.0% in women under 35. A subgroup of women who received oral papaverine at the time of quinacrine insertion had lower pregnancy rates, with a cumulative uncorrected rate of 5.3% at 4 years among women of all ages. CONCLUSION(S): Efficacy of quinacrine appears reasonable for two insertions of quinacrine in women 35 and older. It may be possible to improve efficacy by the use of papaverine or the Hieu insertion technique.

Long-term follow-up after quinacrine sterilization in Vietnam. Part II: interim safety analysis.

OBJECTIVE: To determine the long-term safety of nonsurgical sterilization with quinacrine. DESIGN: Observational cohort study. SETTING: Rural provinces in northern Vietnam. PATIENT(S): Two thousand eight hundred forty women who had had quinacrine insertions and an age-matched comparison group of 1,658 women who had an intrauterine device (IUD) insertion between 1989 and 1993. METHOD(S): Interviews in 1994, 1995, and 1996 and review of available medical records. This is a planned interim analysis. MAIN OUTCOME MEASURE(S): Ectopic pregnancies and the occurrence of other adverse health events. RESULT(S): Over 90% of women were interviewed at least once. Despite matching on age, the groups differed on baseline parity. The ectopic pregnancy rates were similar after either one or two insertions and were similar to the rate of ectopic pregnancies after surgical sterilization in the United States. The quinacrine group reported more gynecologic health problems than the IUD group. However, after correcting for information bias, there was no dose-response effect between the one- and two-insertion quinacrine groups, suggesting the possibility of recall bias or differing baseline health status. CONCLUSION(S): Ectopic pregnancies do not appear to be increased compared with U.S. surgical sterilization rates. The data on other adverse events are more difficult to interpret.

Frequent re-infection in a community with hyperendemic gonorrhoea and chlamydia: appropriate clinical actions.

In a cohort of 1200 individuals experiencing an index infection of gonorrhoea or chlamydia in a rural North Carolina county, we studied the risk factors for re-infection within 16 months. The occurrence of asymptomatic re-infection was estimated from a sample of controls. Re-infection with either of the two STDs occurred in one-quarter (24%) of the study participants and 22% of the controls. The factors associated with re-infection were age less than 25 years, African-American race, male sex, and infection prior to the index infection. The behavioural and attitudinal variables tested were not associated with re-infection. The patterns of re-infection in this study do not provide guidance for targeting resources toward a subgroup of the clinic population. Structuring clinical services to make them more available and acceptable to all potential clinic clients can contribute to decreasing the duration of infections. Lowering the community prevalence in this way will then decrease the likelihood of re-infection rates.

Echocardiographic predictors of clinical outcome in patients with left ventricular dysfunction enrolled in the SOLVD registry and trials: significance of left ventricular hypertrophy. Studies of Left Ventricular Dysfunction.

OBJECTIVES: To assess the relation of left ventricular (LV) and left atrial (LA) dimensions, ejection fraction (EF) and LV mass to subsequent clinical outcome of patients with LV dysfunction enrolled in the Studies of Left Ventricular Dysfunction (SOLVD) Registry and Trials. BACKGROUND: Data are lacking on the relation of LV mass to prognosis in patients with LV dysfunction and on the interaction of LV mass with other measurements of LV size and function as they relate to clinical outcome. METHODS: A cohort of 1,172 patients enrolled in the SOLVD Trials (n = 577) and Registry (n = 595) had baseline echocardiographic measurements and follow-up for 1 year. RESULTS: After adjusting for age, New York Heart Association (NYHA) functional class, Trial vs. Registry and ischemic etiology, a 1-SD difference in EF was inversely associated with an increased risk of death (risk ratio, 1.62; p = 0.0008) and cardiovascular (CV) hospitalization (risk ratio, 1.59; p = 0.0001). Consequently, the other echo parameters were adjusted for EF in addition to age, NYHA functional class, Trial vs. Registry and ischemic etiology. A 1-SD difference in LV mass was associated with increased risk of death (risk ratio of 1.3, p = 0.012) and CV hospitalization (risk ratio of 1.17, p = 0.018). Similar results were observed with the LA dimension (mortality risk ratio, 1.32; p < 0.02; CV hospitalizations risk ratio, 1.18; p < 0.04). Likewise, LV mass > or =298 g and LA dimension > or =4.17 cm were associated with increased risk of death and CV hospitalization. An end-systolic dimension >5.0 cm was associated with increased mortality only. A protective effect of EF was noted in patients with LV mass > or =298 g (those in the group with EF >35% had lower mortality) but not in the group with LV mass <298 g. CONCLUSIONS: In patients with LV dysfunction enrolled in the SOLVD Registry and Trials, increasing levels of hypertrophy are associated with adverse events. A protective effect of EF was noted in patients with LV mass > or =298 g (those in the group with EF >35% fared better) but not in the group with LV mass <298 g. These data support the development and use of drugs that can inhibit hypertrophy or alter its characteristics.

Experience with IUCD insertion outside of menses in Kenya.

OBJECTIVE: To determine if women receiving intrauterine devices (IUCDs) outside of menses have an acceptable rate of insertion problems and subsequent IUCD-related complications. DESIGN: Cross-sectional and prospective cohort study of insertions at times other than during menses. SETTING: The study was carried out in two government family planning (FP) clinics in Nairobi, Kenya. SUBJECTS: After appropriate pre-test and post-test HIV counselling, 1686 women requesting IUCDs at two FP clinics between 1994 and 1995 in Nairobi were enrolled at baseline into a study examining the effect of human immuno-deficiency virus (HIV) infection on IUCD-related complications. Six hundred and forty nine women (156 HIV-infected and 493 HIV-uninfected) were selected for the four month follow up study. They were classified according to their menstrual cycle status at time of IUCD insertion. MAIN OUTCOME MEASURES: Problems at the time of insertion (pain, bleeding, immediate expulsion) and IUCD-related complications through four months. RESULTS: Rates of immediate insertion problems were low in the women who had insertions during menses (7.0%), outside of menses (4.0%) or had oligomenorrhea/amenorrhea (2.6%). The adjusted odds ratios for IUCD insertion problems outside of menses and in oligomenorrhea/amenorrhea (versus women with insertion during menses) were 0.54 (95 % CI 0.18-1.59) and 0.39 (95% CI 0.12-1.29) respectively. IUCD-related complications were higher in the oligomenorrhea/amenorrhea (11.5%) or insertion outside of menses (6.9%), than the within menses (4.3%) groups. However, the differences were not statistically significant. Adjusted odds ratios for IUCD outside of menses and oligomenorrhoea/amenorrhea groups were 1.65 (95% CI 0.21-12.91) and 2.72 (95% CI 0.34-21.71) respectively. CONCLUSION: The results confirm that the IUCD can be safely inserted outside of menses with minimal insertion difficulties and subsequent complications. Availability of IUCDs outside of menses may enhance IUCD acceptance in Kenya and create better opportunity for visual screening of the cervix for sexually transmitted infections.

A comparative study of the safety and efficacy of FemCap, a new vaginal barrier contraceptive, and the Ortho All-Flex diaphragm. The FemCap Investigators' Group.

The FemCap is a new silicone rubber barrier contraceptive shaped like a sailor's hat, with a dome that covers the cervix, a rim that fits into the fornices, and a brim that conforms to the vaginal walls around the cervix. It was designed to result in fewer dislodgments and less pressure on the urethra than the cervical cap and diaphragm, respectively, and to require less clinician time for fitting. This was a phase II/III, multicenter, randomized, open-label, parallel group study of 841 women at risk for pregnancy. A subset of 42 women at one site underwent colposcopy. Women were randomized to use the FemCap or Ortho All-Flex contraceptive diaphragm, both with 2% nonoxynol-9 spermicide, for 28 weeks. The objectives were to compare the two devices with regard to their safety and acceptability and to determine whether the probability of pregnancy among FemCap users was no worse than that of the diaphragm (meaning not more than 6 percentage points higher). The 6-month Kaplan-Meier cumulative unadjusted typical use pregnancy probabilities were 13.5% among FemCap users and 7.9% among diaphragm users. The adjusted risk of pregnancy among FemCap users was 1.96 times that among diaphragm users, with an upper 95% confidence limit of 3.01. Clinical equivalence (noninferiority) of the FemCap compared with the diaphragm, as defined in this study, would mean that the true risk of pregnancy among FemCap users was no more than 1.73 times the pregnancy risk of diaphragm users. Because the observed upper 95% confidence limit (and even the point estimate) exceeded 1.73, the probability of pregnancy among FemCap users, compared with that among diaphragm users, did not meet the definition of clinical equivalence used in this study. The FemCap was believed to be safe and was associated with significantly fewer urinary tract infections. More women reported problems with the FemCap with regard to insertion, dislodgement, and especially removal, although their general assessments were positive. The two devices were comparable with regard to safety and acceptability, but a 6-point difference in the true 6-month pregnancy probabilities of the two devices could not be ruled out. Further studies are needed to determine whether design modifications can simplify insertion and removal.

Effect of intrauterine device use on cervical shedding of HIV-1 DNA.

OBJECTIVE: Hormonal contraception has been associated with an increased prevalence of cervical shedding of HIV-1 DNA among infected women. We conducted this study to evaluate the effect of the use of an intrauterine device (IUD) on the detection of HIV-1 DNA in cervical secretions. DESIGN: A prospective study of HIV-1-seropositive women undergoing IUD insertion at two public family planning clinics in Nairobi, Kenya. METHODS: Cervical swab samples were collected before IUD insertion and approximately 4 months thereafter for the detection of HIV-1-infected cells using polymerase chain reaction (PCR) amplification of HIV-1 gag DNA sequences. RESULTS: Ninety-eight women were enrolled and followed after IUD insertion. The prevalence of HIV-1 DNA cervical shedding was 50% at baseline and 43% at follow-up [odds ratio (OR) 0.8, 95% confidence interval (CI) 0.5-1.2]. There was no statistically significant difference between the baseline and follow-up shedding rates in a multivariate model that controlled for previous hormonal contraceptive use, condom use, cervical ectopy, friable cervix, cervical infections at an interim visit, and CD4 lymphocyte levels (OR 0.6, 95% CI 0.3-1.1). CONCLUSION: The insertion of an IUD did not significantly alter the prevalence of cervical shedding of HIV-1-infected cells. The use of IUDs, in conjunction with condoms, may be an appropriate method of contraception for HIV-1-infected women from the standpoint of potential infectivity to the male partner through exposure to genital HIV-1.

Use of sexually transmitted disease risk assessment algorithms for selection of intrauterine device candidates.

Sexually transmitted diseases (STD) are an important contraindication for intrauterine device (IUD) insertion. Nevertheless, laboratory testing for STD is not possible in many settings. The objective of this study is to evaluate the use of risk assessment algorithms to predict STD and subsequent IUD-related complications among IUD candidates. Among 615 IUD users in Kenya, the following algorithms were evaluated: 1) an STD algorithm based on US Agency for International Development (USAID) Technical Working Group guidelines: 2) a Centers for Disease Control and Prevention (CDC) algorithm for management of chlamydia; and 3) a data-derived algorithm modeled from study data. Algorithms were evaluated for prediction of chlamydial and gonococcal infection at 1 month and complications (pelvic inflammatory disease [PID], IUD removals, and IUD expulsions) over 4 months. Women with STD were more likely to develop complications than women without STD (19% vs 6%; risk ratio = 2.9; 95% CI 1.3-6.5). For STD prediction, the USAID algorithm was 75% sensitive and 48% specific, with a positive likelihood ratio (LR+) of 1.4. The CDC algorithm was 44% sensitive and 72% specific, LR+ = 1.6. The data-derived algorithm was 91% sensitive and 56% specific, with LR+ = 2.0 and LR- = 0.2. Category-specific LR for this algorithm identified women with very low (< 1%) and very high (29%) infection probabilities. The data-derived algorithm was also the best predictor of IUD-related complications. These results suggest that use of STD algorithms may improve selection of IUD users. Women at high risk for STD could be counseled to avoid IUD, whereas women at moderate risk should be monitored closely and counseled to use condoms.

PIP: This study aimed to evaluate the effectiveness of using risk assessment algorithms in predicting sexually transmitted disease (STD) and subsequent IUD-related complications among IUD candidates. The study population was selected among women who desired an IUD insertion in Nairobi, Kenya. The following algorithms drawn from the study of IUD use and HIV infection among these 615 IUD users were evaluated: 1) an STD algorithm based on US Agency for International Development (USAID) Technical Working Group guidelines; 2) a Centers for Disease Control and Prevention (CDC) algorithm for management of chlamydia; 3) a data-derived algorithm modeled from data. Algorithms were also evaluated for prediction of chlamydial and gonococcal infection at 1 month and complications (pelvic inflammatory disease, IUD removals, and IUD expulsions) at 4 months. Results showed that women with STDs were more likely to develop complications than women without STDs (19% vs. 6% risk ratio = 2.9; 95% CI, 1.3-6.5). In STD prediction, the USAID algorithm was 91% sensitive and 56% specific, with LR+ = 2.0 and LR- = 0.2. Category-specific LR for this algorithm identified women with very low (1%) and very high (29%) infection probabilities. Thus, sexually transmitted disease was associated with increased risk for complications after IUD insertion. Moreover, it may be concluded that simple risk assessment criteria can assist in the identification of women at high and low risk for STD among women presenting for IUD insertion; it may also be concluded that the use of simple risk assessment tools may facilitate the identification of women who require close observation, thus reducing the incidence of IUD-related complications.

Longitudinal evaluation of serovar-specific immunity to Neisseria gonorrhoeae.

The serovars of Neisseria gonorrhoeae that are predominant in a community change over time, a phenomenon that may be due to the development of immunity to repeat infection with the same serovar. This study evaluated the epidemiologic evidence for serovar-specific immunity to N. gonorrhoeae. During a 17-month period in 1992-1994, all clients of a sexually transmitted disease clinic in rural North Carolina underwent genital culture for N. gonorrhoeae. Gonococcal isolates were serotyped according to standard methods. Odds ratios for repeat infection with the same serovar versus any different serovar were calculated on the basis of the distribution of serovars in the community at the time of reinfection. Of 2,838 patients, 608 (21.4%; 427 males and 181 females) were found to be infected with N. gonorrhoeae at the initial visit. Ninety patients (14.8% of the 608) had a total of 112 repeat gonococcal infections. Repeat infection with the same serovar occurred slightly more often than would be expected based on the serovars prevalent in the community at the time of reinfection, though the result was marginally nonsignificant (odds ratio = 1.5, 95% confidence interval 1.0-2.4; p = 0.05). Choosing partners within a sexual network may increase the likelihood of repeat exposure to the same serovar of N. gonorrhoeae. Gonococcal infection did not induce evident immunity to reinfection with the same serovar.

Rural gonorrhea in the southeastern United States: a neglected epidemic?

Some rural counties in the southeastern United States are experiencing high rates of gonorrhea; however, existing knowledge of epidemiologic patterns of gonorrhea within communities is from urban areas. This paper describes the epidemiology of gonorrhea within a rural county of North Carolina and compares it with the patterns described for large cities. Data include gonorrhea reports from private physicians and the county health department from August 11, 1992, to August 10, 1993, and ethnographic interviews. The rate among males (1,602 cases per 100,000 person-years) was twice that among females. The risk of reinfection within 6 months of an initial infection (12.9%) was high compared with risks in urban settings. Although case numbers did not cluster by geographical area as described for some cities, case rates did. Factors favoring transmission in rural communities include greater poverty and fewer health care resources than in urban settings, the exchange of sex for crack cocaine, and a lack of anonymity that may cause some people to avoid seeking treatment or acknowledging risky sexual behaviors in a clinical setting. Addressing high rural rates will entail improving access to care, taking extra measures to ensure confidentiality, and dispelling the myth that high rates are limited to cities.

Patterns of medication use in patients with heart failure: a report from the Registry of Studies of Left Ventricular Dysfunction (SOLVD).

To determine patterns of medication use based on clinical variables in patients with heart failure, we analyzed data from 5,999 patients participating in the Registry of Studies of Left Ventricular Dysfunction (SOLVD). The Registry comprised a broad spectrum of patients with heart failure, including some with predominantly diastolic dysfunction. Drug use was determined in a population cross-sectional manner at the time of identification (74% hospitalized). The median number of drugs per patient was four, with diuretics taken by 62%, digitalis by 45%, angiotensin-converting enzyme inhibitors (ACE-I) by 32%, calcium channel blockers by 36%, antiarrhythmics by 22%, and beta-blockers by 18%. Only 18% were on the combination of ACE-I, diuretic, and digitalis. Stratification for diagnosis, heart failure symptoms, and ejection fractions demonstrated that triple-drug therapy (digitalis, diuretic, and ACE-I) was common only in those with ejection fractions less than .20 and several signs or symptoms of heart failure. Older patients were taking diuretics frequently (73% of patients older than 70 years of age), and our European center used fewer drugs overall, while prescribing digitalis about half as frequently as North American clinics. These data serve as the baseline for analysis of evolving therapeutic practice in patients with heart failure.

Relation of neurohumoral activation to clinical variables and degree of ventricular dysfunction: a report from the Registry of Studies of Left Ventricular Dysfunction. SOLVD Investigators.

OBJECTIVES: This study examined the relation between neurohumoral activation and severity of left ventricular dysfunction and congestive heart failure in a broad group of patients with depressed left ventricular function who were not recruited on the basis of eligibility for a therapeutic trial. BACKGROUND: Previous studies have established the presence of neurohumoral activation in patients with severe congestive heart failure. It is not known whether the activation of these neurohumoral mechanisms is related to an impairment in left ventricular function. METHODS: From the 6,273 patients recruited into the Studies of Left Ventricular Dysfunction Registry (SOLVD), a subgroup of 859 patients were randomly selected, and their plasma norepinephrine, plasma renin activity, arginine vasopressin and atrial natriuretic peptide levels were correlated with clinical findings, New York Heart Association functional class, left ventricular ejection fraction and drug use. RESULTS: There was a weak but significant correlation between ejection fraction and an increase in plasma norepinephrine (rho = -0.18, p < 0.0001), plasma renin activity (rho = -0.24, p < 0.0001) and arginine vasopressin (rho = -0.12, p < 0.003). The only exception was atrial natriuretic peptide, which showed the best correlation to ejection fraction (rho = -0.37, p < 0.0001). Deterioration in functional class was associated more with increases in atrial natriuretic peptide (p = 0.0003) and plasma renin activity (p = 0.0003) and less with an increase in plasma norepinephrine. Of the clinical variables, elevated jugular venous pressure and third heart sound (S3) gallop were significantly associated with increased levels of plasma norepinephrine, plasma renin activity and atrial natriuretic peptide. We then compared the relation of neurohormones with clinical signs, functional status, ejection fraction and drug therapy and controlled for mutual interactive effects. After adjustment, a decrease in ejection fraction was still significantly related to an increase in plasma norepinephrine, plasma renin activity and atrial natriuretic peptide. In contrast, only a difference between functional classes I and III/IV was associated with an increase in plasma renin activity and atrial natriuretic peptide levels. CONCLUSIONS: Neurohumoral activation in patients with heart failure is related to severity of left ventricular functional depression, and this relation is independent of functional class or concomitant drug therapy.

Quality of life among 5,025 patients with left ventricular dysfunction randomized between placebo and enalapril: the Studies of Left Ventricular Dysfunction. The SOLVD Investigators.

OBJECTIVES: This study was performed to assess the quality of life of patients with left ventricular dysfunction for up to 2 years after randomization to enalapril or placebo. BACKGROUND: Previous reports have documented that survival of patients with congestive heart failure can be extended by the angiotensin-converting enzyme inhibitor enalapril. However, it is unknown whether enalapril has a long-term favorable impact on the quality of life in patients with heart failure. METHODS: A brief quality of life questionnaire assessing the quality of life was administered at baseline and at 6 weeks, 1 year and 2 years of follow-up to patients randomized to placebo or enalapril in the Studies of Left Ventricular Dysfunction (SOLVD). Participants had an ejection fraction < or = 0.35, no other serious illnesses and either symptomatic heart failure (treatment trial, n = 2,465) or asymptomatic left ventricular dysfunction (prevention trial, n = 2,560). RESULTS: Among the 14 scales of quality of life, better scores at one or more follow-up intervals were noted in 6 scales in the treatment trial and in 1 scale in the prevention trial among patients assigned to enalapril. Consistent superiority with enalapril at two consecutive follow-up intervals was noted in the treatment trial for social functioning and dyspnea but for no scale in the prevention trial. However, an average of 40% of quality of life responses were missing at 2 years of follow-up because of death or failure to complete the questionnaire. In the treatment trial, survivors with more severe heart failure were less likely to complete the questionnaire. CONCLUSIONS: Modest benefits in quality of life for > or = 1 year occurred when patients with left ventricular dysfunction and symptomatic heart failure were treated with enalapril. No apparent beneficial or adverse effect on quality of life was observed with enalapril in asymptomatic patients with left ventricular dysfunction.

Prediction of mortality and morbidity with a 6-minute walk test in patients with left ventricular dysfunction. SOLVD Investigators.

OBJECTIVE: To study the potential usefulness of the 6-minute walk test, a self-paced submaximal exercise test, as a prognostic indicator in patients with left ventricular dysfunction. DESIGN: Data were collected during a prospective cohort study, the Studies of Left Ventricular Dysfunction (SOLVD) Registry Substudy. SETTING: Twenty tertiary care hospitals in the United States, Canada, and Belgium. PARTICIPANTS: A stratified random sample of 898 patients from the SOLVD Registry who had either radiological evidence of congestive heart failure and/or an ejection fraction of 0.45 or less were enrolled in the substudy and underwent a detailed clinical evaluation including a 6-minute walk test. Patients were followed up for a mean of 242 days. OUTCOME MEASURES: Mortality and hospitalization. RESULTS: During follow-up, 52 walk-test participants (6.2%) died and 252 (30.3%) were hospitalized. Hospitalization for congestive heart failure occurred in 78 participants (9.4%), and the combined endpoint of death or hospitalization for congestive heart failure occurred in 114 walk-test participants (13.7%). Compared with the highest performance level, patients in the lowest performance level had a significantly greater chance of dying (10.23% vs 2.99%; P = .01), of being hospitalized (40.91% vs 19.90%; P = .002), and of being hospitalized for heart failure (22.16% vs 1.99%; P < .0001). In a logistic regression model, ejection fraction and distance walked were equally strong and independent predictors of mortality and heart failure hospitalization rates during follow-up. CONCLUSION: The 6-minute walk test is a safe and simple clinical tool that strongly and independently predicts morbidity and mortality in patients with left ventricular dysfunction.

Comparative neurohormonal responses in patients with preserved and impaired left ventricular ejection fraction: results of the Studies of Left Ventricular Dysfunction (SOLVD) Registry. The SOLVD Investigators.

OBJECTIVES: The aim of this study was to determine the differences in neurohumoral responses between patients with pulmonary congestion with and without impaired left ventricular ejection fraction. BACKGROUND: Previous studies have established the presence of neurohumoral activation in patients with congestive heart failure. It is not known whether the activation of these neurohumoral mechanisms is related to the impairment in systolic contractility. METHODS: The 898 patients recruited into the Studies of Left Ventricular Dysfunction (SOLVD) Registry substudy were examined to identify those patients with pulmonary congestion on chest X-ray film who had either impaired (< or = 45%, group I) or preserved (> 45%, group II) left ventricular ejection fraction. Plasma norepinephrine, plasma renin activity, arginine vasopressin and atrial natriuretic peptide levels were measured in these two groups of patients and compared with values in matched control subjects. RESULTS: Distribution of the New York Heart Association symptom classification was the same in the two groups of patients. Compared with control subjects, patients in group II with pulmonary congestion and preserved ejection fraction had no activation of the neurohumoral mechanisms, except for a small but statistically significant increase in arginine vasopressin and plasma renin activity. Compared with patients in group II, those in group I with pulmonary congestion and impaired ejection fraction had significant increases in plasma norepinephrine (p < 0.002), plasma renin activity (p < 0.02) and atrial natriuretic peptide levels (p < 0.0007). When we controlled for baseline differences between groups I and II, the between-group differences in plasma norepinephrine (p < 0.02) and atrial natriuretic peptide (p < 0.002) remained significant. However, plasma renin activity was not significantly different between groups I and II. When the effects of diuretic agents and angiotensin-converting enzyme inhibitors were adjusted, patients with lower ejection fraction were found to have significantly higher plasma norepinephrine and atrial natriuretic peptide levels. CONCLUSIONS: The results point to the importance of the decrease in left ventricular ejection fraction as one of the mechanisms for activation of neurohormones in patients with heart failure.

Recruitment strategies in the studies of left ventricular dysfunction (SOLVD): strategies for screening and enrollment in two concurrent but separate trials. The SOLVD Investigators.

SOLVD was a double-masked, placebo-controlled trial whose initial sample size goal was to randomize 6100 participants into two concurrent trials: treatment and prevention. The objective was to determine if participants with severe left ventricular dysfunction (left ventricular ejection fraction < or = 35%, with congestive heart failure (2569) and participants without overt heart failure (4228) had improved survival with angiotensin-converting enzyme inhibitors. Participants were identified from cardiac catheterization, echocardiography and radionuclide laboratories, and inpatient units. The treatment trial recruitment goal was attained 13 months ahead of schedule while recruitment for the prevention trial was extended 11 months beyond the scheduled time. Recruitment of relatively asymptomatic participants with a low ejection fraction in a hospital-based trial necessitated novel strategies. Coronary care units and clinics for follow-up of acute cardiac conditions, not typically employed in studies of chronic diseases, were useful recruitment sources. Different approaches to encourage participation also needed to be employed. Expanding selected entry criteria was evaluated and the success of varying strategies was reviewed. The authors recommend tailoring of strategies to the target population, staffing flexibility, principal investigator involvement, and broad entry criteria in recruitment activities.

Studies of Left Ventricular Dysfunction (SOLVD) Registry: rationale, design, methods and description of baseline characteristics.

The Studies of Left Ventricular Dysfunction (SOLVD) comprises 2 double-blind, randomized clinical trials to test improved survival by angiotensin-converting enzyme inhibitor in patients with left ventricular dysfunction, with or without congestive heart failure. Patients entering the trials may be a highly selected subset of the population of such patients; those with the worst and best prognosis are likely to be excluded. To obtain the clinical history of a broader group, a registry of 6,273 patients included a relatively unselected cohort of patients with heart failure or left ventricular dysfunction, or both, from SOLVD hospitals. Registry data were obtained from hospital records. Because data collection from medical records may lead to incomplete data and more investigations in "sicker" patients, 898 randomly chosen subjects from different disease strata were seen in clinic where neurohumoral measures, echocardiograms, x-rays and electrocardiograms were obtained, and a 6-minute walking test was performed. The design and methodologic features, and the baseline characteristics of the participants in this 2-tiered registry are described, and its use in complementing the results and interpretation of the SOLVD trials is discussed.

Tyrosine hydroxylase is activated and phosphorylated on different sites in rat pheochromocytoma PC12 cells treated with phorbol ester and forskolin.

Incubation of rat pheochromocytoma PC12 cells with 4 beta-phorbol-12 beta-myristate-13 alpha-acetate (PMA), an activator of Ca2+/phospholipid-dependent protein kinase (protein kinase C), or forskolin, an activator of adenylate cyclase, is associated with increased activity and enhanced phosphorylation of tyrosine hydroxylase. Neither the activation nor increased phosphorylation of tyrosine hydroxylase produced by PMA is dependent on extracellular Ca2+. Both activation and phosphorylation of the enzyme by PMA are inhibited by pretreatment of the cells with trifluoperazine (TFP). Treatment of PC12 cells with 1-oleoyl-2-acetylglycerol also leads to increases in the phosphorylation and enzymatic activity of tyrosine hydroxylase; 1,2-diolein and 1,3-diolein are ineffective. The effects of forskolin on the activation and phosphorylation of the enzyme are independent of Ca2+ and are not inhibited by TFP. Forskolin elicits an increase in cyclic AMP levels in PC12 cells. The increases in both cyclic AMP content and the enzymatic activity and phosphorylation of tyrosine hydroxylase following exposure of PC12 cells to different concentrations of forskolin are closely correlated. In contrast, cyclic AMP levels do not increase in cells treated with PMA. Tryptic digestion of the phosphorylated enzyme isolated from untreated cells yields four phosphopeptides separable by HPLC. Incubation of the cells in the presence of the Ca2+ ionophore ionomycin increases the phosphorylation of three of these tryptic peptides. However, in cells treated with either PMA or forskolin, there is an increase in the phosphorylation of only one of these peptides derived from tyrosine hydroxylase. The peptide phosphorylated in PMA-treated cells is different from that phosphorylated in forskolin-treated cells. The latter peptide is identical to the peptide phosphorylated in dibutyryl cyclic AMP-treated cells. These results indicate that tyrosine hydroxylase is activated and phosphorylated on different sites in PC12 cells exposed to PMA and forskolin and that phosphorylation of either of these sites is associated with activation of tyrosine hydroxylase. The results further suggest that cyclic AMP-dependent and Ca2+/phospholipid-dependent protein kinases may play a role in the regulation of tyrosine hydroxylase in PC12 cells.