Quantifying fascial tension in ventral hernia repair and component separation.

BACKGROUND: Excessive fascial tension is a major cause of ventral hernia recurrence. Although hernias are commonly characterized by area, the tension experienced by fascia is directly proportional to the surrounding tissue stiffness. We demonstrate an accurate and simple technique for intra-operative measurement of fascial closing tension and quantify the decrease in tension following Component Separation (CS). METHODS: A tensiometer was created using a spring with a known recoil constant (k) and a surgical clamp. Using Hooke's law (Force = kX; X = spring displacement), fascial tension was calculated. This method was first validated on a bench-top model and then applied to the anterior fascia of 4 fresh cadavers (8 hemi-abdomens) over a range of simulated hernia defect sizes. When fascia could no longer reach midline, CS was performed and measures repeated. Tissue stiffness was calculated by plotting defect size versus resulting tension. RESULTS: Fascial defects ranged from 1- to 18-cm wide with average midline closing tension prior to release 36.1 N (range 17-48) and 8.2 N (range 5-11) after CS, a mean 76% decrease (range 70%-85%). Mean R2 values between defect size and tension for the synthetic and cadaver models were 0.99 (p < 0.01) and 0.91 (p = 0.01; all hemi-abdomen measurements significant). Inter-rater Pearson's correlation consistently found R2 values > 0.95 (p < 0.01) for each hemi-abdomen, showing high precision and reproducibility. CONCLUSION: We have applied a cheap, simple, and precise method to sterilely assess fascial tension during herniorrhaphy and also quantified the decrease in tension following component separation. This technique may be rapidly translated into the operating room with minimal equipment to provide objective data critical for intraoperative decision-making.

Risk for contralateral breast cancer among carriers of the CHEK2*1100delC mutation in the WECARE Study.

The protein encoded by the CHEK2 gene is involved in cellular repair of DNA damage. The truncating mutation, CHEK2*1100delC, seems to increase the risk for breast cancer. We investigated whether the CHEK2*1100delC mutation carrier status increases the risk for asynchronous contralateral breast cancer (CBC) and whether it interacts with radiation therapy (RT) or chemotherapy in regard to CBC risk. The germline mutation frequency was assessed in 708 women with CBC and 1395 women with unilateral breast cancer (UBC) in the Women's Environment, Cancer and Radiation Epidemiology (WECARE) Study whose first primary breast cancer was diagnosed before age 55 years and during 1985--1999. Seven women with CBC (1.0%) and 10 women with UBC (0.7%) were CHEK2*1100delC variant carriers (rate ratio (RR)=1.8, 95% confidence interval (CI)=0.6-5.4 for CBC vs UBC). Carriers who received RT for their first breast cancer, compared with non-carriers not treated with RT, had an RR of developing CBC of 2.6 (95% CI=0.8-8.7). We found no significant associations between the CHEK2*1100delC mutation and CBC overall or among those treated with RT. However, the sampling variability was such that modest increases in risk could not be excluded. Nonetheless, because this is a rare mutation, it is unlikely to explain a major fraction of CBC in the population.

Population-based estimates of breast cancer risks associated with ATM gene variants c.7271T>G and c.1066-6T>G (IVS10-6T>G) from the Breast Cancer Family Registry.

The ATM gene variants segregating in ataxia-telangiectasia families are associated with increased breast cancer risk, but the contribution of specific variants has been difficult to estimate. Previous small studies suggested two functional variants, c.7271T>G and c.1066-6T>G (IVS10-6T>G), are associated with increased risk. Using population-based blood samples we found that 7 out of 3,743 breast cancer cases (0.2%) and 0 out of 1,268 controls were heterozygous for the c.7271T>G allele (P=0.1). In cases, this allele was more prevalent in women with an affected mother (odds ratio [OR]=5.5, 95% confidence interval [CI]=1.2-25.5; P=0.04) and delayed child-bearing (OR=5.1; 95% CI=1.0-25.6; P=0.05). The estimated cumulative breast cancer risk to age 70 years (penetrance) was 52% (95% CI=28-80%; hazard ratio [HR]=8.6; 95% CI=3.9-18.9; P<0.0001). In contrast, 13 of 3,757 breast cancer cases (0.3%) and 10 of 1,268 controls (0.8%) were heterozygous for the c.1066-6T>G allele (OR=0.4; 95% CI=0.2-1.0; P=0.05), and the penetrance was not increased (P=0.5). These findings suggest that although the more common c.1066-6T>G variant is not associated with breast cancer, the rare ATM c.7271T>G variant is associated with a substantially elevated risk. Since c.7271T>G is only one of many rare ATM variants predicted to have deleterious consequences on protein function, an effective means of identifying and grouping these variants is essential to assess the contribution of ATM variants to individual risk and to the incidence of breast cancer in the population.

ATM variants 7271T>G and IVS10-6T>G among women with unilateral and bilateral breast cancer.

Recent reports suggest that two ATM gene mutations, 7271T>G and IVS10-6T>G, are associated with a high risk of breast cancer among multiple-case families. To assess the importance of these two mutations in another 'high-risk' group, young women (under age 51) with multiple primaries, we screened a large population-based series of young women with bilateral breast cancer and compared the frequency of these mutations among similar women diagnosed with unilateral breast cancer. The 1149 women included were enrolled in an ongoing population-based case-control study of the genetic factors that contribute to bilateral breast cancer; they were not selected on the basis of family history of cancer. Screening for 7271T>G and IVS10-6T>G ATM gene mutations was conducted using DHPLC followed by direct sequencing. The 7271T>G mutation was detected in one out of 638 (0.2%) women with unilateral breast cancer and in none of the bilateral cases, and the IVS10-6T>G mutation in one out of 511 (0.2%) bilateral and in eight out of 638 (1.3%) unilateral breast cancer cases. Carriers of either mutation were not limited to women with a family history. Given the likelihood that young women with bilateral breast cancer have a genetic predisposition, the observed mutation distribution is contrary to that expected if these two mutations were to play an important role in breast carcinogenesis among individuals at high risk.

Screening breast cancer patients for ATM mutations and polymorphisms by using denaturing high-performance liquid chromatography.

All 62 coding exons of the ATM gene, along with 10-20 bases of the intronic region flanking each exon, were screened for DNA base sequence alterations by using denaturing high-performance liquid chromatography (DHPLC) in a series of 52 breast cancer patients. Six (12%) of these patients exhibited a total of eight different novel germ-line mutations that do not represent common polymorphisms. Of these, three patients possessed four nonconservative missense mutations while two conservative missense and two synonymous mutations were detected in the other three patients. In addition, 43 patients were found to have a total of 141 DNA sequence variations representing 21 different common polymorphisms and rare variants. An analysis of the relationship between the presence of a novel ATM mutation and either patient demographics or tumor properties demonstrated a significant difference between African Americans (3/7 = 43%) and other ethnic groups (3/45 = 7%, P = 0.026). None of the other characteristics examined was found to be related to mutation status.

The consequence of undertreating breast cancer in the elderly.

BACKGROUND: Recent studies have noted that a large fraction of elderly patients do not receive conventional treatment for breast cancer. The consequences of undertreatment of the elderly have not been adequately assessed. STUDY DESIGN: The senior author's database (PIT) was used to identify women undergoing potentially curative operations for breast cancer between 1978 and 1998. Risk factors, presentation, pathologic findings, treatment, and outcomes of 206 women aged over 70 years were compared with those of 920 younger patients. In addition, conventionally treated and "undertreated" elderly patients were identified, and their characteristics and outcomes were compared. RESULTS: Older patients' cancers were more often visible on mammography, usually as a mass; younger patients' mammograms were less frequently positive, presenting more often with calcifications (p = 0.002). Cancers of the elderly were better differentiated (p < 0.001) and more likely to be estrogen- and progesterone-receptor positive (p < 0.001; p = 0.007). Patients over 70 had fewer mastectomies (19% versus 33%; p < 0.001) and were also less likely to undergo axillary node dissection (71% versus 81%, p = 0.006), postoperative radiation (69% versus 92%, p < 0.001), and chemotherapy (18% versus 48%, p < 0.001). Fifty-seven percent of older patients were treated with tamoxifen compared with 36% of younger patients (p < 0.001). Elderly patients' rates of local and distant recurrence were comparable to those of younger patients after both mastectomy and breast conservation. Ninety-eight patients (54%) over 70 were undertreated by conventional criteria. Undertreated elderly patients were significantly older (78 versus 76 years, p = 0.003), were diagnosed with excisional biopsy more often (69% versus 57%, p = 0.069) and with fine-needle aspiration less frequently (22% versus 38%, p = 0.069), and were more likely to have breast conservation (90% versus 73%, p = 0.004). Local and distant disease-free survival rates of both groups were comparable. Tamoxifen treatment significantly reduced the chance of developing distant metastasis in node-negative elderly patients with invasive tumors (p = 0.028). Omission of chemotherapy had no impact on disease control in the elderly. Axillary node status and estrogen-receptor status were significantly related to local disease-free survival, and axillary node status was significantly related to distant disease-free survival in multivariate analysis in the elderly. CONCLUSIONS: Elderly breast cancer patients are frequently treated with breast conservation, omitting axillary dissection, radiation therapy, and chemotherapy. Despite undertreatment by conventional criteria, the rates of local recurrence and distant metastasis are not increased in comparison with conventionally treated elderly patients. Tamoxifen should be administered to elderly breast cancer patients with invasive tumors because it significantly improves distant control.

p53 mutations in basal cell carcinomas arising in routine users of sunscreens.

Sun exposure histories were obtained from a series of patients age 35 or younger following diagnosis and removal of a basal cell carcinoma (BCC). The DNA was extracted from tumor biopsy samples derived from BCC of 10 patients who reported that they did not use sunscreens during youth (age 18 or younger) and 10 patients who routinely employed sunscreens during this age period. Exons 5-9 of the p53 gene were then amplified in three fragments from these samples using a nested polymerase chain reaction (PCR) approach and screened for mutations using an RNA heteroduplex assay. All PCR products displaying evidence of a mutation were sequenced. It was found that 6 of the 10 patients who were not routine sunscreen users displayed mutations in these p53 exons. All of the mutations were located at dipyrimidine sites, five of the six were C-->T transitions and one mutation was a tandem double mutation, consistent with a role for solar UVB in BCC formation. In contrast, only one p53 mutation was detected in the group of 10 patients who routinely employed sunscreens during childhood and adolescence. Hence, a significantly (P = 0.029) lower level of p53 mutations was detected in the BCC obtained from sunscreen users compared with tumors derived from nonusers. These findings suggest that the mechanisms involved in the etiology of skin carcinogenesis differ in sunscreen users compared with people who did not routinely employ sunscreens. These data are also indicative of a protective effect associated with sunscreen use against the formation of p53 mutations. It is possible that the patients who were diagnosed with BCC despite their use of sunscreens possessed a genetic susceptibility for skin cancer formation and developed BCC through a p53-independent pathway. Alternatively, solar UVA wavelengths, that were generally not blocked by the suncare products employed by the sunscreen users, may have played a significant role in BCC development through induction of a mutation(s) in an oncogene and/or a tumor suppressor gene, other than p53, for these patients.

Oral contraceptive use and other risk factors in relation to HER-2/neu overexpression in breast cancer among young women.

This study was undertaken to explore whether the incidence of breast tumors that overexpress HER-2/neu protein product (HER-2/neu+) is more strongly associated with oral contraceptives (OCs) and other factors than is the incidence of tumors that do not (HER-2/neu-). In a population-based sample of women <45 years, 42.9% (159 of 371) of in situ and invasive breast cancer cases were HER-2/neu+ as assessed by immunohistochemistry in archived tissue. Polytomous logistic regression was used to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) for HER-2/neu+ and HER-2/neu-breast cancer, as compared with 462 population-based controls, in relation to OCs and other factors. The ratio of the ORs (HER-2/neu+ versus HER-2/neu-tumors) was used as an indicator of heterogeneity in risk. There was little heterogeneity in risk for OC use of 6 months or more by HER-2/neu status (age-adjusted ratio of ORs, 1.29; 95% CI, 0.83-2.00). Among early pill users (< or =18 years of age) heterogeneity was apparent (2.39; 95% CI, 1.08-5.30), which was attenuated in a multivariate model (1.99; 95% CI, 0.87-4.54); among cases with estrogen receptor-negative tumors, heterogeneity increased to 5-fold. For other risk factors, there was no marked heterogeneity between + and - tumors for HER-2/neu. In summary, the incidence of breast cancer among younger women in relation to OC use at an early age varied with HER-2/neu status, with the odds ratio for +tumors twice that for -tumors.

PIP: This population-based study was undertaken to address the hypothesis that the incidence of breast tumor with a high HER-2/neu+ protein product was associated with oral contraceptive (OC) use and other risk factors compared with HER-2/neu- tumors. The study was conducted through the collection of archived paraffin-embedded tissue blocks, laboratory evaluation and combined laboratory results with risk factor information. About 159 of 371 (42.9%) in-situ and invasive breast cancer cases showed overexpression of HER-2/neu+ during immunohistochemistry of archived tissue. During the statistical analysis using a polytomous logistic regression, odds ratio (OR) was calculated and 95% confidence interval (CI) for HER-2/neu+ breast cancer and HER-2/neu- breast cancer compared with 401 controls regarding OC use and other risk factors. The OR (HER-2/neu+ vs. HER-2/neu- tumors) was used as an indicator of heterogeneity in risk. There was little heterogeneity in risk for OC use of 6 months or more by HER-2/neu status (age-adjusted OR, 1.29; 95% CI, 0.83-2.00). In early pill users, heterogeneity by HER-2/neu status was apparent (2.39; 95% CI, 1.08-5.30). A 5-fold increase in heterogeneity risk was noted among women with estrogen receptor (ER) negative tumors. In conclusion, the incidence of breast cancer among younger women in relation to OC use at an early age varied with HER-2/neu status, with the OR for positive tumors being twice that for negative tumors.

Cigarette smoking and other risk factors in relation to p53 expression in breast cancer among young women.

p53 mutations may be a fingerprint for cigarette smoking and other environmental carcinogens, including breast carcinogens. This study was undertaken to explore whether p53 mutations are associated with environmental or other suspected or established risk factors for breast cancer. p53 protein detection by immunohistochemistry (which is more easily quantified in large epidemiological studies than are mutations, and are highly correlated with them) was determined for 378 patients from a case-control study of breast cancer. In this population-based sample of women under the age of 45 years, 44.4% (168/378) of the cases had p53 protein detected by immunohistochemistry (p53+). Polytomous logistic regression was used to calculate the odds ratios (ORs) for p53+ and p53- breast cancer, as compared with the controls, in relation to cigarette smoking and other factors. The ratio of the ORs was used as an indicator of heterogeneity in risk for p53+ versus p53- cancer. The ratio of the ORs in a multivariate model was substantially elevated among women with a greater than high school education [2.39; 95% confidence interval (CI), 1.43-4.00], current cigarette smokers (1.96; 95% CI, 1.10-3.52), and users of electric blankets, water beds, or mattresses (1.78; 95% CI, 1.11-2.86). Nonsignificant heterogeneity was noted for family history of breast cancer and ethnicity but not for other known or suspected risk factors. Coupled with the strong biological plausibility of the association, our data support the hypothesis that in breast cancer, as with other tumors, p53 protein immunohistochemical detection may be associated with exposure to environmental carcinogens such as cigarette smoking.

Delay in diagnosis of breast cancer.

OBJECTIVES: To assess the consequences of physician delay in the diagnosis of breast cancer by comparing stage, treatment, and outcome of patients with and without delay, and to identify patient characteristics that may make diagnosis more difficult. SUMMARY BACKGROUND INFORMATION: Delay in diagnosis of breast cancer is the most common clinical scenario resulting in malpractice litigation. METHODS: The records of 1014 patients were reviewed and the events preceding the diagnosis were reconstructed. Accurate assessment of the physician delay in diagnosis could be made for 606 patients, 51 (8%) with physician delay >3 months. Patients with delay were comparable to patients without delay in terms of age, height, weight, age at menarche, pregnancies, children, proportion in menopause, age at menopause, and family history of breast cancer. RESULTS: Thirty-six percent of patients who had a delay in diagnosis had normal mammograms versus 7% of patients without delay. Cancers in patients with delay were significantly larger on average than in those without delay, but there were no significant differences in pathology, differentiation, nodal status, TNM stage, treatment, or outcome. CONCLUSIONS: Physician delay in the diagnosis of breast cancer is common, and patients with delay are similar to patients without delay, although they are more likely to have normal mammograms. The consequences of physician delay in terms of stage at diagnosis, treatment, and outcome were not statistically significant.

The epidemiology of Her-2/neu and P53 in breast cancer.

Breast cancer is an etiologically heterogeneous disease with marked geographical variations. Joint consideration of the relationship between specific molecular alterations and known or suspected epidemiologic risk factors for this disease should help distinguish subgroups of women that are at elevated risk of developing breast cancer. In this article, we present a comprehensive literature review of the etiologic and prognostic roles of Her-2/neu and P53 among women. In addition, we discuss the advantages and limitations of using biomarkers in epidemiological studies. We conclude that more research is needed to understand the complex relationships between genetic alterations and etiologic risk factors for breast cancer.

Risk factors predicting the incidence of second primary breast cancer among women diagnosed with a first primary breast cancer.

This study examined risk factors for development of a contralateral breast cancer among 4,660 US women diagnosed with a first primary breast cancer between 1980 and 1982. The authors believe it to be the first prospective cohort study on this topic that has employed direct patient interviews. All subjects were interviewed within 6 months of the diagnosis of their initial tumor as part of the multi-center, population-based, case-control Cancer and Steroid Hormone Study, and they were followed until the end of 1986 through the Surveillance, Epidemiology, and End Results program. Exclusive of those diagnosed during the initial 6 months after diagnosis of a first primary, 136 second primary breast cancers were identified. Proportional hazards models were used to assess the independent effects of multiple predictors. Specific risk factors evaluated included: age at diagnosis of first primary, exposure to exogenous hormones, menstrual and reproductive histories, tumor characteristics, demographic variables, and treatment modalities. The age-specific incidence rates of second primary breast cancer were higher in all age categories than are the incidence rates of breast cancer in the general population, yet the age at diagnosis of first primary breast cancer was not an important predictor of contralateral breast cancer. The risk of contralateral breast cancer was increased among cohort members who reported a personal history of benign breast biopsy (multivariable-adjusted rate ratio (RR) = 1.69, 95% confidence interval (CI) 1.13-2.53) and in those with an initial tumor that was classified as lobular carcinoma (multivariable-adjusted RR = 1.96, 95% CI 1.17-3.27). Treatment with chemotherapy for the first primary was associated with a lower risk of development of a second breast cancer (multivariable-adjusted RR = 0.56, 95% CI 0.33-0.96), while radiation therapy had little effect on the risk (multivariable-adjusted RR = 1.19, 95% CI 0.78-1.80).

The genetic epidemiology of second primary breast cancer.

It is well established that women with a family history of breast cancer run a higher risk of breast cancer than do women without a family history. The evidence, however, is less clear regarding a possible association between a family history of breast cancer and risk of second primaries. The purpose of this prospective study was to estimate the risk for second primary breast cancer associated with having a family history of breast, endometrial, and ovarian cancers. A cohort of 4,660 women with a first primary breast cancer diagnosed between 1980 and 1982 were interviewed as part of the Cancer and Steroid Hormone Study, a multi-center population-based case-control study, and followed through eight Surveillance, Epidemiology, and End Results (SEER) program registries for 4 to 6 years. Of these women, 136 developed a second primary breast cancer in the contralateral breast at least 6 months after diagnosis of the first primary. Cox proportional hazards modeling techniques were used to model the time to onset of second primary breast cancer while adjusting for multiple predictors. The risk of contralateral breast cancer was elevated among cohort members who reported a history of breast cancer in a first-degree relative (multivariable-adjusted rate ratio (RR) = 1.91, 95% confidence interval (CI) = 1.22-2.99). Early age at onset (< 46 years) in the relative further increased the risk of developing contralateral breast cancer (sister: multivariable-adjusted RR = 3.36, 95% CI 1.62-6.98; mother: multivariable-adjusted RR = 2.35, 95% CI 1.02-5.43). Bilateral breast cancer in mothers was also associated with more than a two and a half-fold increase in risk (multivariable-adjusted RR = 2.55, 95% CI 1.02-6.35). The association between family history of breast cancer and risk of contralateral breast cancer did not vary substantially according to age at onset of the first primary breast cancer. The age-adjusted rate ratio for development of a second primary breast cancer among women with a first-degree relative with endometrial cancer was 2.13 (95% CI 1.04-4.35), while the corresponding rate ratio among women with a family history of ovarian cancer was 1.69 (95% CI 0.42-6.83). There was little evidence that age at onset among the relatives with endometrial or ovarian cancer affected the risk. Some of these findings have not been previously reported and need replication in future studies.

Prognostic importance of the serum magnesium concentration in patients with congestive heart failure.

Magnesium abnormalities are common in patients with congestive heart failure but the clinical and prognostic significance of an abnormal serum magnesium concentration in this disorder has not been investigated. Therefore, the relation between serum magnesium concentration and the clinical characteristics and long-term outcome of 199 patients with chronic heart failure was evaluated. The serum magnesium concentration was less than 1.6 mEq/liter in 38 patients (19%), within the normal range in 134 patients (67%) and greater than 2.1 mEq/liter in 27 patients (14%). Patients with hypomagnesemia had more frequent ventricular premature complexes and episodes of ventricular tachycardia than did patients with a normal serum magnesium concentration (p less than 0.05). Even though the two groups were similar with respect to severity of heart failure and neurohormonal variables, patients with a low serum magnesium concentration had a significantly worse prognosis during long-term follow-up (45% versus 71% 1 year survival, p less than 0.05). Patients with hypermagnesemia had more severe symptoms, greater neurohormonal activation and worse renal function than did patients with a normal serum magnesium concentration but tended to have fewer ventricular arrhythmias. Hypermagnesemic patients had a worse prognosis than did those with a normal magnesium concentration (37% versus 71% 1 year survival, p less than 0.05). In conclusion, the measurement of serum magnesium concentration provides important clinical and prognostic information in patients with chronic heart failure.

Prognostic importance of the immediate hemodynamic response to nifedipine in patients with severe left ventricular dysfunction.

To determine the clinical significance of the occurrence of hemodynamic deterioration after the administration of calcium channel blocking drugs, nifedipine (20 mg orally) was administered to 29 patients with severe left ventricular dysfunction. Thirteen patients showed hemodynamic improvement with the drug (Group 1), as shown by a notable increase in cardiac index associated with a modest decrease in mean arterial pressure. The other 16 patients exhibited hemodynamic deterioration after nifedipine (Group 2), as reflected by a decline in right and left ventricular stroke work indexes accompanied by a marked hypotensive response. These differences were not related to differences in the peripheral vascular response to nifedipine, because both groups showed similar decreases in systemic and pulmonary vascular resistances. Groups 1 (hemodynamic improvement) and 2 (hemodynamic deterioration) were similar with respect to all demographic variables and pretreatment left ventricular performance (cardiac index, left ventricular filling pressure and systemic vascular resistance). Yet, the 1 year actuarial survival in patients in Group 1 was substantially better than that in patients in Group 2 (67 versus 23%, p = 0.009). Group 2, however, had higher values for plasma renin activity (17.7 +/- 6.0 versus 4.3 +/- 1.4 mg/ml per h, p less than 0.05), lower values for serum sodium concentration (134.6 +/- 1.2 versus 139.2 +/- 0.6 mEq/liter, p less than 0.05) and higher values for mean right atrial pressure (15.8 +/- 2.0 versus 7.9 +/- 1.4 mm Hg, p less than 0.01) than did patients in Group 1.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of neurohormonal mechanisms in determining survival in patients with severe chronic heart failure.

Support for the concept that neurohormonal mechanisms play an important role in determining the survival of patients with severe chronic heart failure is derived from two lines of evidence: circulating levels of neurohormones are markedly elevated in patients who have a poor long-term prognosis and the survival of high-risk patients may be favorably modified by treatment with specific neurohormonal antagonists. Plasma norepinephrine is a major prognostic factor in patients with severe chronic heart failure, the most markedly elevated levels being observed in patients with the most unfavorable long-term prognosis. Data from uncontrolled studies suggest that low-dose beta-blockade may improve the survival of patients with dilated cardiomyopathy. Similar trends were noted in the Beta-Blocker Heart Attack Trial, in which patients with congestive heart failure before or accompanying their acute myocardial infarction experienced a significant reduction in sudden death when treated with beta-blockers. In contrast, there appeared to be little selective benefit in patients without heart failure, who presumably had low circulating levels of catecholamines. Similarly, serum sodium concentration is a major prognostic factor in patients with severe chronic heart failure, the shortest survival being observed in patients with the most severe hyponatremia. The poor long-term outcome of hyponatremic patients appears to be related to the marked elevation of plasma renin activity in these individuals, since (in retrospective studies) hyponatremic patients appeared to fare significantly better when treated with converting-enzyme inhibitors than when treated with vasodilator drugs that did not interfere with angiotensin II formation. In contrast, there appeared to be no selective benefit of converting-enzyme inhibition on the survival of patients with a normal serum sodium concentration, in whom plasma renin activity was low. These data suggest that neurohormonal systems may exert a deleterious effect on the survival of some patients with severe chronic heart failure, which may be favorably modified by long-term treatment with specific neurohormonal antagonists.