The impact of pre-eclampsia definitions on the identification of adverse outcome risk in hypertensive pregnancy - analyses from the CHIPS trial (Control of Hypertension in Pregnancy Study).

OBJECTIVE: To examine the association between pre-eclampsia definition and pregnancy outcome. DESIGN: Secondary analysis of Control of Hypertension in Pregnancy Study (CHIPS) trial data. SETTING: International multicentre randomised controlled trial (RCT). POPULATION: In all, 987 women with non-severe non-proteinuric pregnancy hypertension. METHODS: We evaluated the association between pre-eclampsia definitions and adverse pregnancy outcomes, stratified by hypertension type and blood pressure control. MAIN OUTCOME MEASURES: Main CHIPS trial outcomes: primary (perinatal loss or high-level neonatal care for >48 hours), secondary (serious maternal complications), birthweight <10th centile, severe maternal hypertension, delivery at <34 or <37 weeks, and maternal hospitalisation before birth. RESULTS: Of 979/987 women with informative data, 280 (28.6%) progressed to pre-eclampsia defined restrictively by new proteinuria, and 471 (48.1%) to pre-eclampsia defined broadly as proteinuria or one/more maternal symptoms, signs or abnormal laboratory tests. The broad (versus restrictive) definition had significantly higher sensitivities (range 62-79% versus 36-50%), lower specificities (range 53-65% versus 72-82%), and similar or higher diagnostic odds ratios and 'true-positive' to 'false-positive' ratios. Stratified analyses showed similar results. Addition of available fetoplacental manifestations (stillbirth or birthweight <10th centile) to the broad pre-eclampsia definition improved sensitivity (74-87%). CONCLUSIONS: A broad (versus restrictive) pre-eclampsia definition better identifies women who develop adverse pregnancy outcomes. These findings should be replicated in a prospective study within routine healthcare to ensure that the anticipated increase in surveillance and intervention in a larger number of women with pre-eclampsia is associated with improved outcomes, reasonable costs and congruence with women's values. TWEETABLE ABSTRACT: A broad (versus restrictive) pre-eclampsia definition better identifies the risk of adverse pregnancy outcomes.

Survival Analysis in the Presence of Competing Risks: The Example of Waitlisted Kidney Transplant Candidates.

Competing events (or risks) preclude the observation of an event of interest or alter the probability of the event's occurrence and are commonly encountered in transplant outcomes research. Transplantation, for example, is a competing event for death on the waiting list because receiving a transplant may significantly decrease the risk of long-term mortality. In a typical analysis of time-to-event data, competing events may be censored or incorporated into composite end points; however, the presence of competing events violates the assumption of "independent censoring," which is the basis of standard survival analysis techniques. The use of composite end points disregards the possibility that competing events may be related to the exposure in a way that is different from the other components of the composite. Using data from the Scientific Registry of Transplant Recipients, this paper reviews the principles of competing risks analysis; outlines approaches for analyzing data with competing events (cause-specific and subdistribution hazards models); compares the estimates obtained from standard survival analysis, which handle competing events as censoring events; discusses the appropriate settings in which each of the two approaches could be used; and contrasts their interpretation.

Control of Hypertension In Pregnancy Study randomised controlled trial-are the results dependent on the choice of labetalol or methyldopa?

OBJECTIVE: To determine whether the difference in outcomes between 'less tight' (target diastolic blood pressure [dBP] of 100 mmHg) versus 'tight' control (target dBP of 85 mmHg) in the CHIPS Trial (ISRCTN 71416914, http://pre-empt.cfri.ca/;CHIPS) depended on the choice of labetalol or methyldopa, the two most commonly used antihypertensive agents in CHIPS. DESIGN: Secondary analysis of CHIPS Trial data. SETTING: International multicentre randomised controlled trial (94 sites, 15 countries). POPULATION OR SAMPLE: A total of 987 women with non-severe non-proteinuric pregnancy hypertension. METHODS: Logistic regression was used for comparisons of 'less tight' versus 'tight' control among women treated with labetalol (but not methydopa) versus methyldopa (but not labetalol). Analyses were adjusted for the influence of baseline factors, including use of any antihypertensive therapy at randomisation. MAIN OUTCOME MEASURES: Main CHIPS Trial outcomes: primary (perinatal loss or high-level neonatal care for > 48 hours), secondary (serious maternal complications), birthweight < 10th centile, severe maternal hypertension, pre-eclampsia, and delivery at < 34 or < 37 weeks. RESULTS: Of 987 women in CHIPS, antihypertensive therapy was taken by 566 women at randomisation (labetalol 111 ['less tight'] versus 127 ['tight'] or methyldopa 126 ['less tight'] versus 117 ['tight']) and 815 women after randomisation (labetalol 186 ['less tight'] versus 247 ['tight'] and methyldopa by 98 ['less tight'] versus 126 ['tight']). Following adjustment, odds ratios for outcomes in 'less tight' versus 'tight' control were similar between antihypertensive groups according to 'at randomisation' and 'after randomisation' therapy. CONCLUSION: Outcomes for 'less tight' versus 'tight' control were not dependent on use of methyldopa or labetalol. TWEETABLE ABSTRACT: In the CHIPS Trial, maternal and infant outcomes were not dependent on use of labetalol or methyldopa.

Do labetalol and methyldopa have different effects on pregnancy outcome? Analysis of data from the Control of Hypertension In Pregnancy Study (CHIPS) trial.

OBJECTIVE: To compare pregnancy outcomes, accounting for allocated group, between methyldopa-treated and labetalol-treated women in the CHIPS Trial (ISRCTN 71416914) of 'less tight' versus 'tight' control of pregnancy hypertension. DESIGN: Secondary analysis of CHIPS Trial cohort. SETTING: International randomised controlled trial (94 sites, 15 countries). POPULATION OR SAMPLE: Of 987 CHIPS recruits, 481/566 (85.0%) women treated with antihypertensive therapy at randomisation. Of 981 (99.4%) women followed to delivery, 656/745 (88.1%) treated postrandomisation. METHODS: Logistic regression to compare outcomes among women who took methyldopa or labetalol, adjusted for the influence of baseline factors. MAIN OUTCOME MEASURES: CHIPS primary (perinatal loss or high level neonatal care for >48 hours) and secondary (serious maternal complications) outcomes, birthweight <10th centile, severe maternal hypertension, pre-eclampsia and delivery at <34 or <37 weeks. RESULTS: Methyldopa and labetalol were used commonly at randomisation (243/987, 24.6% and 238/987, 24.6%, respectively) and post-randomisation (224/981, 22.8% and 433/981, 44.1%, respectively). Following adjusted analyses, methyldopa (versus labetalol) at randomisation was associated with fewer babies with birthweight <10th centile [adjusted odds ratio (aOR) 0.48; 95% CI 0.20-0.87]. Methyldopa (versus labetalol) postrandomisation was associated with fewer CHIPS primary outcomes (aOR 0.64; 95% CI 0.40-1.00), birthweight <10th centile (aOR 0.54; 95% CI 0.32-0.92), severe hypertension (aOR 0.51; 95% CI 0.31-0.83), pre-eclampsia (aOR 0.55; 95% CI 0.36-0.85), and delivery at <34 weeks (aOR 0.53; 95% CI 0.29-0.96) or <37 weeks (aOR 0.55; 95% CI 0.35-0.85). CONCLUSION: These nonrandomised comparisons are subject to residual confounding, but women treated with methyldopa (versus labetalol), particularly those with pre-existing hypertension, may have had better outcomes. TWEETABLE ABSTRACT: There was no evidence that women treated with methyldopa versus labetalol had worse outcomes.

HLA-DR and -DQ eplet mismatches and transplant glomerulopathy: a nested case-control study.

We conducted a nested case-control study from a cohort of adult kidney transplant recipients to assess the risk of transplant glomerulopathy (TG) as a function of donor and recipient HLA-DR and -DQ incompatibility at the eplet level. Cases (n = 52) were defined as patients diagnosed with transplant glomerulopathy based on biopsies showing glomerular basement membrane duplication without immune complex deposition. Controls (n = 104) with a similar follow-up from transplantation were randomly selected from the remaining cohort. HLAMatchmaker was used to ascertain the number of DRB1/3/4/5, DQA1 and DQB1 related eplet mismatches (eplet load). Multivariable conditional logistic regression models demonstrated an increase in the odds of TG (odds ratios [OR] of 2.84 [95% confidence interval (CI): 1.03, 7.84] and 4.62 [95% CI: 1.51, 14.14]) in the presence of 27-43 and >43 HLA-DR + DQ related eplet mismatches versus <27 eplet mismatches, respectively. When the eplet load was modeled as a continuous variable, the OR for TG was 1.25 (95% CI: 1.04, 1.50) for every 10 additional HLA-DR + DQ eplet mismatches. Our study suggests that minimization of HLA-DR + DQ eplet mismatches may decrease the incidence of transplant glomerulopathy diagnosed by indication biopsies. The role of eplet immunogenicity/antigenicity as determinants of allograft outcomes requires further study.

Shift in sleep apnoea type in heart failure patients in the CANPAP trial.

In patients with heart failure (HF), the predominant type of sleep apnoea can change over time in association with alterations in circulation time. The aim of this study was to determine whether, in some patients with HF, a spontaneous shift from mainly central (>50% central events) to mainly obstructive (>50% obstructive events) sleep apnoea (CSA and OSA, respectively) over time coincides with improvement in left ventricular ejection fraction (LVEF). Therefore, sleep studies and LVEFs of HF patients with CSA from the control arm of the Canadian Continuous Positive Airway Pressure for Patients with Central Sleep Apnea and Heart Failure (CANPAP) trial were examined to determine whether some converted to mainly OSA and, if so, whether this was associated with an increase in LVEF. Of 98 patients with follow-up sleep studies and LVEFs, 18 converted spontaneously to predominantly OSA. Compared with those in the nonconversion group, those in the conversion group had a significantly greater increase in the LVEF (2.8% versus -0.07%) and a significantly greater fall in the lung-to-ear circulation time (-7.6 s versus 0.6 s). In patients with HF, spontaneous conversion from predominantly CSA to OSA is associated with an improvement in left ventricular systolic function. Future studies will be necessary to further examine this relationship.

The Control of Hypertension In Pregnancy Study pilot trial.

OBJECTIVE: To determine whether 'less tight' (versus 'tight') control of nonsevere hypertension results in a difference in diastolic blood pressure (dBP) between groups. DESIGN: Randomised controlled trial (ISRCTN#57277508). SETTING: Seventeen obstetric centres in Canada, Australia, New Zealand, and UK. POPULATION: Inclusion: pregnant women, dBP 90-109 mmHg, pre-existing/gestational hypertension; live fetus(es); and 20-33(+6) weeks. Exclusion: systolic blood pressure > or = 170 mmHg and proteinuria, contraindication, or major fetal anomaly. METHODS: Randomisation to less tight (target dBP, 100 mmHg) or tight (target dBP, 85 mmHg) blood pressure control. MAIN OUTCOME MEASURES: Primary: mean dBP at 28, 32 and 36 weeks. Secondary: clinician compliance and women's satisfaction. Other: serious perinatal and maternal complications. RESULTS: A total of 132 women were randomised to less tight (n = 66; seven had no study visit) or tight control (n= 66; one was lost to follow up; seven had no study visit). Mean dBP was significantly lower with tight control: -3.5 mmHg, 95% credible interval (-6.4, -0.6). Clinician compliance was 79% in both groups. Women were satisfied with their care. With less tight (versus tight) control, the rates of other treatments and outcomes were the following: post-randomisation antenatal antihypertensive medication use: 46 (69.7%) versus 58 (89.2%), severe hypertension: 38 (57.6%) versus 26 (40.0%), proteinuria: 16 (24.2%) versus 20 (30.8%), serious maternal complications: 3 (4.6%) versus 2 (3.1%), preterm birth: 24 (36.4%) versus 26 (40.0%), birthweight: 2675 +/- 858 versus 2501 +/- 855 g, neonatal intensive care unit (NICU) admission: 15 (22.7%) versus 22 (34.4%), and serious perinatal complications: 9 (13.6%) versus 14 (21.5%). CONCLUSION: The CHIPS pilot trial confirms the feasibility and importance of a large definitive trial to determine the effects of less tight control on serious perinatal and maternal complications.

Women's views of their experiences in the CHIPS (Control of Hypertension in Pregnancy Study) Pilot Trial.

BACKGROUND: Satisfaction with maternity care is strongly related to the patient-caregiver relationship and involvement in the decision-making process. We sought to compare women's views about their care in a randomized trial of 'less tight' vs. 'tight' control of non-proteinuric pre-existing or gestational hypertension in pregnancy. METHODS: In the CHIPS Pilot Trial, women completed a postpartum questionnaire to assess their likes and dislikes about their blood pressure (BP) management and trial participation. Comparisons were descriptive. RESULTS: Baseline information was similar for the 'less tight' and 'tight' control groups. Of 132 women, 126 (95.5%) from 17 centers completed a postpartum questionnaire, usually within days of delivery. At least 90% of women in both groups were satisfied with their care, and would be willing to participate again or recommend participation to a friend. Women in both the 'less tight' and 'tight' groups were satisfied with BP management (98.4% vs. 95.1%), and the frequency of tests of maternal and fetal well being. Half of women in both groups perceived that their BP was too high and that caregivers thought that their BP was too high. More women in the 'less tight' (vs. the 'tight') control group took less medication than expected (71.7% vs. 38.2%). More women in the 'tight' (vs. the 'less tight') group took more medication than they expected (60.0% vs. 22.2%). At least 60% of all women used home BP monitoring. CONCLUSION: In the CHIPS Pilot Trial, while women stated that they were satisfied with their BP management and care, a surprising 50% in both groups thought that their BP was too high. The majority of women used home BP monitoring, the role of which must be further defined in hypertensive pregnancies.

Effects of continuous positive airway pressure on cardiovascular outcomes in heart failure patients with and without Cheyne-Stokes respiration.

BACKGROUND: Continuous positive airway pressure (CPAP) improves cardiac function in patients with congestive heart failure (CHF) who also have Cheyne-Stokes respiration and central sleep apnea (CSR-CSA). However, the effects of CPAP in CHF patients without CSR-CSA have not been tested, and the long-term effects of this treatment on clinical cardiovascular outcomes are unknown. METHODS AND RESULTS: We conducted a randomized, controlled trial in which 66 patients with CHF (29 with and 37 without CSR-CSA) were randomized to either a group that received CPAP nightly or to a control group. Change in left ventricular ejection fraction (LVEF) from baseline to 3 months and the combined mortality-cardiac transplantation rate over the median 2.2-year follow-up period were compared between the CPAP-treated and control groups. For the entire group of patients, CPAP had no significant effect on LVEF, but it was associated with a 60% relative risk reduction (95% confidence interval, 2% to 64%) in mortality-cardiac transplantation rate in patients who complied with CPAP therapy. Stratified analysis of patients with and without CSR-CSA revealed that those with CSR-CSA experienced both a significant improvement in LVEF at 3 months and a relative risk reduction of 81% (95% confidence interval, 26% to 95%) in the mortality-cardiac transplantation rate of those who used CPAP. CPAP had no significant effect on either of these outcomes in patients without CSR-CSA. CONCLUSIONS: CPAP improves cardiac function in CHF patients with CSR-CSA but not in those without it. Although not definitive, our findings also suggest that CPAP can reduce the combined mortality-cardiac transplantation rate in those CHF patients with CSR-CSA who comply with therapy.

Pathogenesis of obstructive sleep apnoea in hypertensive patients: role of fluid retention and nocturnal rostral fluid shift.

Obstructive sleep apnoea (OSA) is highly prevalent in hypertensive patients, particularly those with drug resistance. Evidence from animal experiments, epidemiologic studies and clinical trials strongly suggest a causal link. Mechanistic studies argue for increased sympathetic neural activity and endothelial dysfunction. However, disturbances in fluid volume regulation and distribution may also be involved in the pathogenesis of these two conditions. Several studies have shown a high prevalence of OSA in fluid-retaining states including hypertension, a direct relationship between the severity of OSA and the volume of fluid displaced from the legs to the neck during sleep, and a decrease in upper airway cross-sectional area in response to graded lower body positive pressure. Treatments targeting fluid retention and redistribution, including diuretics, mineralocorticoid antagonists, exercise, and possibly renal denervation lower blood pressure and reduce the apnoea-hypopnoea index, a measure of OSA severity. From these observations, it has been postulated that during the daytime, excess fluid collects in the lower extremities due to gravity, and on lying down overnight is redistributed rostrally to the neck, where it may narrow the upper airway and increase its collapsibility, predisposing to OSA when pharyngeal dilator muscle activity decreases during sleep. This article discusses the associations between OSA and hypertension and reviews the evidence for fluid accumulation and its nocturnal rostral redistribution in the pathogenesis of OSA in hypertensive patients.

Prevalence of Type A behavior in untreated hypertensive individuals.

Type A behavior has been associated with coronary heart disease as well as high cholesterol and smoking, major risk factors for coronary heart disease, but the data indicating a similar association with hypertension are inconsistent. Since past studies have usually based hypertension on a single blood pressure assessment or have often included treated hypertensive patients, this inconsistency is not surprising. The current study compared the prevalence of Type A behavior (assessed by Rosenman's structured interview) between 109 untreated hypertensive subjects and 109 age-, sex-, ethnic-, and occupation-matched normotensive subjects. Hypertension status was based on five repeated assessments over a 5-month period. Results indicated that Type A behavior is more prevalent in untreated, mildly hypertensive employed individuals than occupationally matched normotensive subjects. Type A component analysis confirmed the importance of hostility and certain vigorous voice stylistics in predicting cardiovascular conditions. These findings, taken together with the evidence linking Type A behavior with high cholesterol and cigarette smoking, further support the view that this behavior pattern is associated with increased risk of coronary heart disease.

Clinical effectiveness and cost-effectiveness of monitoring blood pressure of hypertensive employees at work.

In this randomized controlled trial, the value of using occupational health nurses (OHNs) to monitor the care of hypertensive employees at work was compared with regular care (RC) delivered in the community. One year after entry, the blood pressure level, medication history, compliance with treatment, and cost of hypertensive care of the participants were determined by independent evaluators. The reduction in diastolic blood pressure (DBP), the measure of effectiveness, was 10.5 +/- 1.1 mm Hg (mean +/- SEM) in the OHN group and 7.7 +/- 1.1 mm Hg in the RC group, and the proportion under good blood pressure control was 41.8% and 31.0% respectively. These between-group differences were not statistically significant. Although the employees in the OHN group were more medicated and had a lower treatment dropout rate, neither difference was statistically significant. In addition, the proportion of employees who were compliant with prescribed medication was virtually identical in both groups. The cost of the care received by employees in the OHN group of $ 404.14 for the year was substantially higher than that of $ 250.15 in the RC group with the difference principally related to the cost of visiting the OHNs and a significant difference in drug cost (p less than 0.006). The incremental cost-effectiveness (C/E) ratio of $ 53.67 per mm Hg DBP reduction per year for onsite blood pressure monitoring was higher than the base C/E ratio of $ 32.65 per mm Hg for regular care. Our findings indicate that monitoring the blood pressure of hypertensive employees at work is neither clinically effective nor cost-effective.(ABSTRACT TRUNCATED AT 250 WORDS)

Cost-effectiveness of a worksite hypertension treatment program.

The cost-effectiveness of treating hypertension at the patient's place of work was compared in a randomized controlled trial with care delivered in a community. The average total cost per patient for worksite care in this 12-month study was not significantly different from that for regular care ($242.86 +/- 6.94 vs $211.34 +/- 18.66, mean +/- SEM). The worksite health system cost was significantly more expensive ($197.36 +/- 4.99 vs $129.33 +/- 13.34, p less than 0.001) but the patient cost was significantly less ($45.40 +/- 3.23 vs $82.00 +/- 6.20, p less than 0.01). The mean reduction in diastolic blood pressure (BP) at the year-end assessment was significantly greater in the worksite group (12.1 +/- 0.6 vs 6.5 +/- 0.6 mm Hg, p less than 0.001). The incremental cost-effectiveness ratio of $5.63 per mm Hg for worksite care was less than the base cost-effectiveness ratio of $32.51 per mm Hg for regular care, indicating that the worksite program was substantially more cost-effective. Our findings support health policies that favor allocating resources to work-based hypertension treatment programs for the target group identified in this study.

Insulin blunts the natriuretic action of atrial natriuretic peptide in hypertension.

Hyperinsulinemia and insulin resistance are implicated in the etiology of hypertension, but the mechanisms involved have not been established. The objectives of this study were to determine whether untreated essential hypertensive patients are more sensitive to the antinatriuretic action of insulin and more resistant to the counteracting natriuretic effect of atrial natriuretic peptide in contrast to age- and sex-matched normotensive control subjects. Urinary sodium excretion was measured at baseline, during hyperinsulinemic euglycemic clamp, and during coadministration of insulin and atrial natriuretic peptide. Baseline urinary sodium excretion was not significantly different in the normotensive subjects (415 +/- 47 mumol/min, n = 12) and hypertensive patients (381 +/- 18 mumol/min, n = 10); with the institution of insulin infusion, there was a similar and significant decline from baseline (P < .001) to 289 +/- 35 mumol/min in normotensive subjects and 235 +/- 17 mumol/min in hypertensive patients. Atrial natriuretic peptide was able to oppose the antinatriuretic action of insulin in normotensive subjects, increasing urinary sodium excretion significantly to a mean level of 352 +/- 31 mumol/min (P < .05), which did not differ significantly from baseline. In the hypertensive group, atrial natriuretic peptide infusion had no effect on urinary sodium excretion (238 +/- 18 mumol/min), and the difference from baseline remained highly significant (P < .001). The hypertensive patients were significantly less insulin sensitive than their normotensive counterparts, as reflected by a lower glucose utilization rate and higher mean baseline plasma insulin level (P < .05 for each).(ABSTRACT TRUNCATED AT 250 WORDS)

Dietary salt restriction increases vascular insulin resistance.

BACKGROUND: Recent studies have shown that insulin has a direct vasodilator effect and that vascular sensitivity to insulin is impaired in hypertension. How the vasodilator effect of insulin is regulated physiologically is unknown. It has been appreciated that salt restriction may have adverse effects on glucose and lipid metabolism--processes regulated by insulin. To determine whether dietary salt restriction might affect vascular sensitivity to insulin, we studied 13 subjects (including eight borderline hypertensive subjects and five normotensive subjects) after 1 week of a normal sodium diet (240 mEq/day) and after 1 week of a low-sodium diet (20 mEq/day) with a randomized, double-blind crossover design. METHODS AND RESULTS: Vascular sensitivity to insulin was assessed with the dorsal hand vein linear variable differential transformer technique. When the "normal" salt diet was given, vascular sensitivity for insulin was significantly less (i.e., dose that produced the half-maximal response [ED50] insulin was higher) in hypertensive subjects (ED50 insulin for hypertensive subjects, 5.75 milliunits (mU)/min; ED50 insulin for normotensive subjects, 0.23 mU/min; p < 0.05). Vascular sensitivity to insulin was inversely correlated with mean arterial pressure and plasma norepinephrine concentration. When the low salt diet was given, vascular sensitivity to insulin decreased in both the normotensive and hypertensive groups, paralleling an increase in plasma norepinephrine. Blood pressure was not significantly decreased by reducing salt intake. CONCLUSION: In these younger normotensive and hypertensive subjects, dietary salt restriction increases resistance to the vasodilating effects of insulin.

L-deprenyl in Alzheimer's disease: cognitive and behavioral effects.

BACKGROUND: Short-term studies of L-deprenyl in Alzheimer's disease (AD) suggest a beneficial effect, whereas longer-term studies are less convincing. Accordingly, we undertook a 6-month, randomized, double-blind, placebo-controlled clinical trial to assess the potential benefit of L-deprenyl in AD. METHODS: Sixty subjects were assigned to L-deprenyl (10 mg daily) or placebo. After 4 weeks of single-blind placebo, 51 subjects entered the double-blind phase. The Brief Psychiatric Rating Scale (BPRS) was the primary outcome measure. Secondary outcome measures were the Mini-Mental State Examination, Global Deterioration Scale, Alzheimer's Disease Assessment Scale (noncognitive), Cornell Scale for Depression in Dementia, Buschke Selective Reminding Test (BSRT), Relative's Assessment of Global Symptomatology-Elderly (RAGS-E), Controlled Oral Word Association Test, and Modified Continuous Performance Test. In addition, several exploratory tasks were included for future hypothesis testing. RESULTS: We found no significant differences between the L-deprenyl and placebo groups on the primary or secondary measures. However, several measures appeared to be sensitive to change over time, including the total score on the BPRS and some of its components as well as parts of the BSRT and the RAGS-E. CONCLUSION: Oral L-deprenyl provides no detectable benefit on general behavior, neuropsychiatric symptoms, or cognitive function in AD after 6 months of treatment. Protocols for future drug studies should utilize measures that are sensitive to change over time such as the BPRS.

Role of atrial natriuretic peptide in the natriuretic response to central volume expansion induced by head-out water immersion in sodium-retaining cirrhotic subjects.

PURPOSE: It is possible that abnormalities in atrial natriuretic peptide may be involved in the pathogenesis of sodium retention in edema states. We performed a study in a group of 12 sodium-retaining cirrhotic subjects to determine the role of this peptide in mediating differences in the natriuretic response to central volume expansion induced by head-out water immersion. PATIENTS AND METHODS: Each patient was maintained for seven days on a 20-mmol sodium intake, and then studied on both control and immersion days. On each day, measurements of the following were obtained: plasma atrial natriuretic peptide, hematocrit, electrolytes, creatinine, plasma renin activity, serum aldosterone, urinary cyclic guanosine monophosphate (cGMP), blood pressure, and pulse rate. RESULTS: In six subjects, immersion resulted in a marked natriuresis sufficient to induce negative sodium balance by the third hour, and these subjects were termed "responders." In these six patients, baseline pre-immersion levels of plasma renin activity and serum aldosterone were all below 3 ng/liter/second and 4 nmol/liter, respectively. In the other six subjects, the natriuretic response to immersion was markedly blunted and insufficient to induce negative sodium balance, and these subjects were termed "non-responders." In these subjects, baseline pre-immersion levels of plasma renin activity and aldosterone were all above 3.5 ng/liter/second and 5 nmol/liter, respectively, and were significantly elevated compared with the responders, and compared with the normal range for control subjects consuming the same sodium intake. In both groups of cirrhotic subjects, baseline levels of plasma atrial natriuretic peptide and cGMP excretion were significantly and comparably elevated compared with the normal range for control subjects ingesting the same sodium intake. Despite the marked difference in the natriuretic response to immersion in both responders and non-responders, there was a significant and comparable further elevation of plasma atrial natriuretic peptide and urinary cGMP excretion during immersion, compared with the control day. CONCLUSION: These results suggest that the relative resistance to the natriuretic action of atrial natriuretic peptide in the non-responders compared with the responders is mediated by anti-natriuretic factors acting at a level parallel with or beyond atrial natriuretic peptide release or coupling to its cGMP-linked receptors.

Acute effects of peritoneovenous shunting on plasma atrial natriuretic peptide in cirrhotic patients with massive refractory ascites.

Plasma immunoreactive alpha-human atrial natriuretic peptide (ANP) was measured in six cirrhotic patients with massive refractory ascites, under strict metabolic conditions, while they were receiving a 20-meq sodium diet, both before and at two-hour intervals for eight hours following peritoneovenous shunting (PVS). The mean preoperative level of ANP was 75 +/- 18 pg/ml, which was found to be significantly higher than the normal range for this laboratory (8 to 24 pg/ml) (p less than 0.05). This value was also significantly higher than the value of 21 +/- 5 pg/ml (p less than 0.05) obtained in six patients with cirrhosis but without ascites. Following shunt insertion, an immediate natriuresis and diuresis were observed in five of the six cirrhotic patients with refractory ascites. In these five, right atrial pressure and ANP rose immediately, followed by a rise in the level of urinary cyclic guanosine monophosphate. The sixth subject had a delayed rise in right atrial pressure, and correspondingly the rise in ANP, the diuresis, and natriuresis were delayed. The changes in ANP following PVS were positively correlated with changes in right atrial pressure (p less than 0.05), urinary cyclic guanosine monophosphate (p less than 0.05), urinary sodium excretion (p less than 0.05), and urine volume (p less than 0.01). These results suggest that ANP may be important in mediating the acute response to PVS.

The effect of patient 'familiarity' with blood pressure assessment on the accuracy of follow-up readings.

The fall in blood pressure that is commonly observed when groups of hypertensive individuals are followed without treatment is usually ascribed to two sources: regression towards the mean and increasing familiarity of the subject with the assessment process. Any effect of the latter process could bias the results of controlled studies in which one group is more frequently assessed than the other, a common situation in community trials. To assess the effect of familiarity, we randomly allocated 116 untreated, mildly hypertensive subjects to three-monthly or yearly assessments. At an independent, blind, year end assessment, both groups showed statistically significant reductions in diastolic blood pressure (P less than 0.001) of 8.4 +/- 1.2 (s.e.m.) and 7.6 +/- 1.6 mmHg respectively, but the difference between the groups was not significant (P = 0.682). We conclude that 'familiarity' does not play an important role in the reduction of blood pressure in long-term follow-up studies of hypertensive subjects.

Hypertension aggregates in families of kidney stone patients with high urinary excretion of uric acid.

OBJECTIVE: To determine whether kidney stone disease (KSD) and hypertension (HTN) share a common familial component that is determined by a specific urinary biochemical abnormality. DESIGN: Familial aggregation study. PATIENTS: Two hundred and twelve KSD patients, aged 18-50 years, collected a 24-h urine sample to measure the urinary excretion of uric acid, calcium, oxalate, magnesium and citrate, and were interviewed about the occurrence of HTN among first-degree relatives. OUTCOME: Positive family history (FHx) of HTN defined as two or more relatives with HTN, and HTN occurring in the fathers, mothers and siblings. RESULTS: Positive FHx of HTN was significantly associated with increasing urinary excretion of uric acid (P = 0.03) but not with the excretion of the other substances. When the patients were divided into those with and without hyperuricosuria, the adjusted odds ratio (OR) for positive FHx of HTN in a hyperuricosuric KSD patient was 3.8 (95% CI, 1.22-11.66). Separate analysis on the occurrence of HTN in the fathers, mothers and siblings of the probands indicated that hyperuricosuria is positively related to HTN occurring in the siblings of the patients (P < 0.001) but not in the fathers or in the mothers. The adjusted OR for HTN occurring in siblings of hyperuricosuric patients compared with siblings of non-hyperuricosuric patients was 3.8 (2.12-6.67). CONCLUSION: Siblings of KSD patients with hyperuricosuria had a significantly increased prevalence of HTN that could not be accounted for by age, family size, body-mass index and personal history of HTN of the probands. Additional studies need to be undertaken to determine whether this familial clustering has a genetic or environmental origin.