Adrenomedullin, endothelin, neuropeptide Y, atrial, brain, and C-natriuretic prohormone peptides compared as early heart failure indicators

OBJECTIVES:The present investigation was designed to determine the best endogenous plasma marker of early congestive heart failure (CHF). METHODS: Forty volunteers with mild CHF (New York Heart Association Class I, n = 12), moderate (Class II, n = 8), or severe (Class III and Class IV, each = n of 5) and 10 age-matched healthy individuals had the simultaneous evaluation of their respective plasma samples by the following radioimmunoassays: atrial natriuretic peptide, ANP; three N-terminal ANP prohormone assays, i.e., proANPs 1-30, 31-67, and 79-98 with the numbers referring to their amino acid (a.a.) sequences in their 126 a.a. prohormone; brain (BNP) and C-natriuretic peptides; N-terminal BNP prohormone; adrenomedullin; neuropeptide Y and endothelin. RESULTS: ProANPs 31-67, 1-30 and 79-98 had 100% (P = 0.01), 83% (P = 0.09) and 50% (P = 0.74) sensitivity in differentiating Class I CHF subjects from healthy subjects. The ANP, BNP, NT-proBNP, CNP, adrenomedullin, neuropeptide Y, and endothelin assays could not differentiate mild CHF subjects from healthy individuals. Logistic regression analysis revealed that only proANP 31-67 significantly (P = 0.0001) discriminated between early CHF (5226 +/- 377 pg/ml) and healthy individuals (1595 +/- 157 pg/ml). The positive and negative predicative values of proANP 31-67 were excellent (100% for each). The peptides measured in these assays were found to be independent markers of CHF with respect to left ventricular ejection fraction. CONCLUSIONS: ProANPs 31-67 is the most sensitive marker in discriminating NYHA Class I CHF subjects from healthy individuals. The ANP, BNP, NT-proBNP, CNP, adrenomedullin, neuropeptide Y and endothelin radioimmunoassays cannot discern mild CHF. These peptides are independent of left ventricular ejection fraction.     

Increased brain natriuretic peptide and atrial natriuretic peptide plasma concentrations in dialysis-dependent chronic renal failure and in patients with elevated left ventricular filling pressure

Brain natriuretic peptide (BNP) and atrial natriuretic peptide (ANP) plasma concentrations were measured in patients with dialysis-dependent chronic renal failure and in patients with coronary artery disease exhibiting normal or elevated left ventricular end-diastolic pressure (LVEDP) (n = 30 each). Blood samples were obtained from the arterial line of the arteriovenous shunt before, 2 h after the beginning of, and at the end of hemodialysis in patients with chronic renal failure. In patients with coronary artery disease arterial blood samples were collected during cardiac catheterization. BNP and ANP concentrations were determined by radioimmunoassay after Sep Pak C18 extraction. BNP and ANP concentrations decreased significantly (P < 0.001) during hemodialysis (BNP: 192.1 +/- 24.9, 178.6 +/- 23.0, 167.2 +/- 21.8 pg/ml; ANP: 240.2 +/- 28.7, 166.7 +/- 21.3, 133.0 +/- 15.5 pg/ml). The decrease in BNP plasma concentrations, however, was less marked than that in ANP plasma levels (BNP 13.5 +/- 1.8%, ANP 40.2 +/- 3.5%; P < 0.001). Plasma BNP and ANP concentrations were 10.7 +/- 1.0 and 60.3 +/- 4.0 pg/ml in patients with normal LVEDP and 31.7 +/- 3.6 and 118.3 +/- 9.4 pg/ml in patients with elevated LVEDP. These data demonstrate that BNP and ANP levels are strongly elevated in patients with dialysis-dependent chronic renal failure compared to patients with normal LVEDP (BNP 15.6-fold, ANP 2.2-fold, after hemodialysis; P < 0.001) or elevated LVEDP (BNP 6.1-fold, ANP 2.0-fold, before hemodialysis; P < 0.001), and that the elevation in BNP concentrations was more pronounced than that in ANP plasma concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)     

High- versus low-dose ACE inhibition in chronic heart failure: a double-blind, placebo-controlled study of imidapril

OBJECTIVES: To determine dose-related clinical and neurohumoral effects of angiotensin-converting enzyme (ACE) inhibitors in patients with chronic heart failure (CHF), we conducted a double-blind, placebo-controlled, randomized study of three doses (2.5 mg, 5 mg and 10 mg) of the long-acting ACE inhibitor imidapril. BACKGROUND: The ACE inhibitors have become a cornerstone in the treatment of CHF, but whether high doses are more effective than low doses has not been fully elucidated, nor have the mechanisms involved in such a dose-related effect. METHODS: In a parallel group comparison, the effects of three doses of imidapril were examined. We studied 244 patients with mild to moderate CHF (New York Heart Association class II-III: +/-80%/20%), who were stable on digoxin and diuretics. Patients were treated for 12 weeks, and the main end points were exercise capacity and plasma neurohormones. RESULTS: At baseline, the four treatment groups were well-matched for demographic variables. Of the 244 patients, 25 dropped out: 3 patients died, and 9 developed progressive CHF (3/182 patients on imidapril vs. 6/62 patients on placebo, p < 0.05). Exercise time increased 45 s in the 10-mg group (p = 0.02 vs. placebo), but it did not significantly change in the 5-mg (+16 s), and 2.5-mg (+11 s) imidapril group, compared to placebo (+3 s). Physical working capacity also increased in a dose-related manner. Plasma brain and atrial natriuretic peptide decreased (p < 0.05 for linear trend), while (nor)epinephrine, aldosterone and endothelin were not significantly affected. Renin increased in a dose-related manner, but plasma ACE activity was suppressed similarly (+/-60%) on all three doses. CONCLUSIONS: Already within 3 months after treatment initiation, high-dose ACE inhibition (with imidapril) is superior to low-dose. This is reflected by a more pronounced effect on exercise capacity and some of the neurohormones, but it does not appear to be related to the extent of suppression of plasma ACE.     

Temporal patterns in the medical treatment of congestive heart failure with angiotensin-converting enzyme inhibitors in older adults, 1989 through 1995

BACKGROUND: Evidence from clinical trials in the past decade has consistently shown that angiotensin-converting enzyme (ACE) inhibitors reduce morbidity and mortality in patients with congestive heart failure (CHF). The extent to which clinical practice has adopted ACE inhibitor therapy is unknown. METHODS: The Cardiovascular Health Study is a prospective observational study of 5201 community-dwelling adults aged 65 years and older. Prevalent CHF cases were identified on study entry (from June 10, 1989, through May 31, 1990) and incident CHF cases were identified throughout 5 years of follow-up. Medication data were collected from annual medication inventories. The percentage of patients with CHF using ACE inhibitors was calculated at each annual examination. Temporal trends in CHF treatment with ACE inhibitors between June 10, 1989, through May 31, 1990, and June 1, 1994, through May 31, 1995, were analyzed. RESULTS: Use of ACE inhibitors to treat CHF increased slightly over time among prevalent cases at each annual examination: 26% of prevalent CHF cases were treated in 1989-1990 compared with 36% of prevalent cases in 1994-1995. This 10% increase was statistically significant (P<.01). Participants with low ejection fractions were 2 times more likely to be treated with ACE inhibitors than were those with normal ejection fraction and this tendency did not change over time. Among cases newly diagnosed in the year before the 1990-1991 examination, 42% were using ACE inhibitors; among those newly diagnosed in the year before 1994-1995, 40% were using ACE inhibitors. This 2% decrease was not statistically significant (P=.68). CONCLUSION: These findings suggest that, while the medical management of CHF with ACE inhibitors has increased modestly over time in prevalent cases, these drugs may still be underused, especially among incident cases.     

Captopril and spironolactone therapy for refractory congestive heart failure

Short- and long-term clinical effects of the angiotensin-converting enzyme (ACE) inhibitor captopril in severe congestive heart failure (CHF) were evaluated during a 3-year open study of 124 inpatients with New York Heart Association (NYHA) functional class III or IV CHF refractory to treatment with cardiac glycosides and high doses of loop diuretics. Captopril was added to each patient's regimen, which comprised combinations of furosemide (124 patients), digitalis (117 patients), and spironolactone (90 patients). By the end of the first month of captopril administration, improvement in NYHA functional class was seen in 89 patients (72%). During the first year of captopril treatment, the number of hospital admissions and hospital days declined significantly (p < 0.001) and functional class improved significantly (p < 0.001). Although most patients tolerated captopril well, 44% experienced hypotension, which in 10% of patients necessitated termination of captopril therapy. Although mean serum potassium levels tended to increase, serious hyperkalemia did not occur. After 1 year, a subset of 30 patients who had not initially received spironolactone deteriorated clinically and manifested increasing urinary aldosterone levels. Hypotension precluded increasing the captopril dose, but introduction of spironolactone improved clinical status in this cohort. The results suggest that rational therapy for severe CHF includes addition of the aldosterone antagonist spironolactone to low doses of captopril (or another ACE inhibitor) and high doses of loop diuretics, provided renal function is adequate.     

Effect of indomethacin on the renal response to angiotensin II receptor blockade in healthy subjects

BACKGROUND: Non-steroidal anti-inflammatory drugs are known to promote sodium retention and to blunt the blood pressure lowering effects of several classes of antihypertensive agents including beta-blockers, diuretics and angiotensin converting enzyme (ACE) inhibitors. The purpose of the present study was to investigate the acute and sustained effects of indomethacin on the renal response to the angiotensin II receptor antagonist valsartan and to the ACE inhibitor enalapril. METHODS: Twenty normotensive subjects maintained on fixed sodium intake (100 mmol sodium/day) were randomized to receive for one week: valsartan 80 mg o.d., enalapril 20 mg o.d., valsartan 80 mg o.d. + indomethacin 50 mg bid and enalapril 20 mg o.d. + indomethacin 50 mg bid. This single-blind study was designed as a parallel (valsartan vs. enalapril) and cross-over trial (valsartan or enalapril vs. valsartan + indomethacin or enalapril + indomethacin). Renal hemodynamics and urinary electrolyte excretion were measured for six hours after the first and seventh administration of each treatment regimen. RESULTS: The results show that valsartan and enalapril have comparable renal effects characterized by no change in glomerular filtration rate and significant increases in renal plasma flow and sodium excretion. The valsartan- and enalapril-induced renal vasodilation is not significantly blunted by indomethacin. However, indomethacin similarly abolishes the natriuresis induced by the angiotensin II antagonist and the ACE inhibitor. CONCLUSIONS: This observation suggests that although angiotensin receptor antagonists do not affect prostaglandin metabolism, the administration of a non-steroidal anti-inflammatory drug blunts the natriuretic response to angiotensin receptor blockade.     

Congestive heart failure in the community: a study of all incident cases in Olmsted County, Minnesota, in 1991

BACKGROUND: Data are limited regarding the classification and prognosis of patients with congestive heart failure (CHF) in the community. METHODS AND RESULTS: Using the resources of the Rochester Epidemiology Project, we evaluated all patients receiving a first diagnosis of CHF in Olmsted County, Minnesota, in 1991 (n=216). Among these patients, 88% were >/=65 years and 49% were >/=80 years of age. The prognosis of patients with a new diagnosis of CHF was poor; survival was 86+/-2% at 3 months, 76+/-3% at 1 year, and 35+/-3% at 5 years. Of the 216 patients, 137 (63%) had an assessment of ejection fraction. In these patients, systolic function was preserved (ejection fraction >/=50%) in 59 (43%) and reduced (ejection fraction <50%) in 78 (57%). Survival adjusted for age, sex, NYHA class, and coronary artery disease was not significantly different between patients with preserved and those with reduced systolic function (relative risk, 0.80; P=0.369). ACE inhibitors were used in only 44% of the total population with CHF. CONCLUSIONS: The present study reports the clinical characteristics and natural history of CHF as it presents in the community in the vasodilator era. CHF is a disease of the "very elderly," frequently occurs in the setting of normal ejection fraction, and has a poor prognosis, regardless of the level of systolic function. Diagnostic and therapeutic methods are underused in the community.     

Upregulation of angiotensin converting enzyme by atrial natriuretic peptide and cyclic GMP in human endothelial cells

OBJECTIVE: To examine the role of atrial natriuretic peptide (ANP) and cyclic GMP in the regulation of angiotensin converting enzyme (ACE) in cultured human endothelial cells. METHODS: Cultured endothelial cells from human umbilical veins (HUVEC) were treated with ANP (0.3-30 nM), 8-Br-cGMP (1-100 microM), Rp-8-Br-PET-cGMPS (1 microM), or the phosphodiesterase inhibitors, zaprinast (10-100 microM), dipyridamole (1-10 microM), or isobutyl methyl xanthine (IBMX, 0.1-0.5 mM). ACE amounts were measured by inhibitor binding assay and cellular cGMP levels by radioimmunoassay. RESULTS: ANP caused a dose dependent increase in ACE measured in intact endothelial cell culture. The stimulatory effect of ANP was blocked by Rp-8-Br-PET-cGMPS, a protein kinase G inhibitor. The cyclic GMP analog, 8-Br-cGMP and the cyclic GMP specific phosphodiesterase inhibitor, zaprinast, both increased ACE. Increase of ACE was also caused by nonspecific phosphodiesterase inhibitors, dipyridamole and IBMX. Intracellular cGMP levels were shown to increase by ANP, and phosphodiesterase inhibitors. CONCLUSIONS: These data suggest that cGMP is an intracellular mediator regulating ACE and that ANP induced increase of ACE is mediated via a cGMP dependent mechanism.     

MR guidance of laser disc decompression: preliminary in vivo experience

BACKGROUND: The mechanism of atrial natriuretic peptide (ANP) release has been difficult to demonstrate in patient studies because of inaccuracies in measuring atrial volumes using conventional techniques. METHODS: Magnetic resonance imaging was performed in 28 clinically stable patients (New York Heart Association class 3) with chronic heart failure to determine right atrial (RA), left atrial (LA), and ventricular volumes. In addition, right heart catheterization was serially performed and plasma ANP levels (in picograms per milliliter) were drawn from the right atrium. RESULTS: Five patients had to be excluded from data analysis for technical reasons. The remaining 23 patients had the following hemodynamic measurements (mean +/- SD): RA mean pressure 7+/-5 mm Hg, pulmonary artery mean pressure 28+/-10, pulmonary capillary wedge pressure 21+/-8 mm Hg, and cardiac index 2.9+/-1.4 (L/min/m2), respectively. Plasma ANP levels were significantly elevated at 162+/-117 (normal range 20 to 65 pg/ml, p < 0.05), as were LA and RA volumes compared with healthy controls (RA volume 128+/-64 ml vs 82+/-25 ml, p < 0.05; LA volume 157+/-54 ml vs 71+/-24 ml, p < 0.01, respectively). ANP showed a stronger relation with atrial volumes (RA volume, r = 0.91, p = 0.0001; LA volume, r = 0.80, p = 0.001) than with atrial pressures (RA mean pressure, r = 0.45, p = 0.03; pulmonary capillary wedge pressure, r = 0.67, p = 0.001). A subgroup analysis of patients with increased RA or LA volumes (>1 SD of mean of controls) revealed a stronger relation between ANP and RA volumes than between ANP and LA volumes. CONCLUSIONS: These data suggest that increased right heart volume with subsequent increased atrial stretch is the major determinant for ANP release in patients with stable CHF.     

Effects of exercise on plasma level of brain natriuretic peptide in congestive heart failure with and without left ventricular dysfunction

This study was designed to determine whether plasma brain natriuretic peptide (BNP) increases in response to exercise in patients with congestive heart failure and to show what kind of hemodynamic abnormalities induce increased secretion of BNP during exercise. Plasma levels of atrial natriuretic peptide (ANP) and BNP and hemodynamic parameters were measured during upright bicycle exercise tests in seven patients with dilated cardiomyopathy and nine with mitral stenosis. At rest, there were no intergroup differences in cardiac output or pulmonary capillary wedge pressure; however, the group with dilated cardiomyopathy had higher left ventricular end-diastolic pressures and lower left ventricular ejection fractions than did the group with mitral stenosis. Plasma ANP levels were comparable between the dilated cardiomyopathy group (170 +/- 77 [SE] pg/ml) and the mitral stenosis group (106 +/- 33 pg/ml) (p, not significant), whereas BNP was significantly higher in the dilated cardiomyopathy group (221 +/- 80 pg/ml) than in the other group (37 +/- 10 pg/ml) (p < 0.05). The plasma concentration of BNP but not of ANP significantly correlated with left ventricular end-diastolic pressure and volume. Exercise increased plasma ANP and BNP in the two groups. The dilated cardiomyopathy group had a larger increment in BNP (+157 +/- 79 pg/ml) than did the mitral stenosis group (+17 +/- 5 pg/ml) (p < 0.05), although the increase in pulmonary capillary wedge pressure was greater in the mitral stenosis group. Thus exercise increases plasma levels of BNP, and impaired left ventricular function may be a main factor in the greater increment in BNP during exercise in patients with congestive heart failure.     

Metrological analysis of measuring systems in testing an anticipatory reaction to the position of a moving object

This study compared the effects of angiotensin converting enzyme (ACE) inhibitors captopril versus enalapril on left ventricular (LV) muscle mass and LV systolic and diastolic function in 58 patients with primary glomerulonephritis and moderate chronic renal failure. The design was a 6-8 week titration phase and 6-month maintenance phase. Mean myocardial mass calculated by M-mode echocardiography in the captopril group was 153 +/- 26 g/m2 before, and 130 +/- 14 g/m2 after 6 months of treatment, in enalapril group 147 +/- 22 g/m2 before, and 126 +/- 23 g/m2 after 6 months of treatment (p < 0.05). LV ejection fraction, early and late transmitral flow velocities and early to late LV inflow velocities ratio were not significantly affected by both ACE inhibitors.     

Altered myocardial phenotype after mechanical support in human beings with advanced cardiomyopathy

BACKGROUND: Left ventricular assist devices (LVAD) provide lifesaving circulatory support to patients awaiting heart transplantation. To date, the extent to which sustained mechanical unloading alters the phenotype of pathologic myocardial hypertrophy in dilated cardiomyopathy is unknown. METHODS: We examined left ventricular size, myocyte and myocardial immunoreactivity for atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) in eight patients with advanced dilated cardiomyopathy before and after LVAD support. The mean duration of congestive heart failure was 18 +/- 5 months, and LVAD support averaged 42 +/- 4 days before heart transplantation. RESULTS: Echocardiographically determined left ventricular mass decreased from 505 +/- 83 to 297 +/- 52 gm (p < 0.05) during LVAD support, whereas minimum myocyte diameter decreased from 28.1 +/- 0.9 to 21.7 +/- 0.6 microns (p < 0.01) in transmural myocardial tissue specimens. Overall left ventricular ANP immunopositivity decreased from 48% at LVAD placement to 12% at transplantation (p < 0.05), whereas BNP immunopositivity decreased from 28% to 4% after LVAD support. Moreover, a gradient of ANP and BNP immunostaining from subendocardium to epicardium observed before mechanical unloading diminished after LVAD support. Analysis of the relationship between left ventricular mass and ANP immunopositivity revealed a close and highly significant correlation between these variables. CONCLUSIONS: These studies demonstrate remarkable left ventricular plasticity even in the presence of advanced cardiomyopathy. Parallel reductions in myocardial mass and myocyte size with reductions in ventricular ANP and BNP immunostaining indicate a novel regression of the phenotype of pathologic hypertrophy within the human myocardium after LVAD support.     

Blood levels of erythropoietin in congestive heart failure and correlation with clinical, hemodynamic, and hormonal profiles

Plasma levels of erythropoietin (mU/ml) were measured in patients with congestive heart failure (CHF) (n = 108) and in a control group of normal subjects (n = 45). In normal subjects, plasma levels of erythropoietin were 1.9 +/- 0.2. In patients with CHF, plasma levels of erythropoietin increased progressively according to New York Heart Association (NYHA) class (I: 1.4 +/- 0.2, n = 28; II: 5.4 +/- 0.8, n = 27; III: 9.6 +/- 2, n = 32; IV: 34 +/- 8, n = 21; F = 57.7, p < 0.001) and were significantly higher in NYHA classes II, III, and IV than in normal subjects. Plasma erythropoietin significantly decreased (from 43 +/- 14 to 12 +/- 3 mU/ml, p < 0.01) in patients with severe CHF (n = 9) when enalapril (20 mg/day administered orally) was added to long-term treatment for 3 weeks. Finally, in a subgroup of patients with NYHA class IV CHF (n = 9) and high plasma erythropoietin levels (37 +/- 9 mU/ml), packed red blood cell volume, assessed by the iodine-125-albumin dilution method, was higher than that in normal subjects (n = 11) (2,616 +/- 235 vs 2,028 +/- 119 ml, p < 0.05). The present study demonstrates that plasma erythropoietin levels are elevated in a large cohort of patients with CHF of varying etiology, and that this increase is related to the progression of the disease. The increase in circulating erythropoietin is associated with augmented packed red blood cell volume in patients with severe CHF. These results suggest a participation of erythropoietin in the complex neurohormonal response that occurs in CHF.     

Plasma levels of natriuretic peptides and adrenomedullin in elderly hypertensive patients: relationships to 24 h blood pressure

OBJECTIVE: The aim of this study was to investigate the relationships between levels of natriuretic peptides and adrenomedullin and 24 h blood pressure levels in elderly hypertensives. DESIGN AND METHODS: We performed both 24 h ambulatory blood pressure monitoring and measurement of plasma levels of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and adrenomedullin in 118 asymptomatic hypertensive elderly (> 60 years old) patients. We classified the subjects into groups with isolated clinic hypertension (n = 40) and sustained hypertension (n = 78). We also measured the levels of these peptides in 37 elderly normotensive subjects. RESULTS: Plasma ANP and BNP levels were slightly increased in patients with isolated clinic hypertension compared with elderly normotensives. Among the hypertensives, plasma ANP and BNP levels were more closely related to 24 h blood pressure levels than to office blood pressure levels. Sustained hypertensives showed significantly increased plasma levels of ANP and BNP compared with isolated clinic hypertensives, while adrenomedullin levels were similar in the two groups. Elderly hypertensives with left ventricular hypertrophy detected by electrocardiography had significantly higher levels of ANP and BNP, and higher BNP/ANP ratios than those without left ventricular hypertrophy, while there was no significant difference in adrenomedullin levels between the two groups. CONCLUSIONS: Our results suggest that measurements of ANP and BNP may be useful in detecting left ventricular hypertrophy and in differentiating isolated clinic hypertension from sustained hypertension in elderly hypertensive patients.     

The clinical relevance of circulating tumor necrosis factor-alpha in acute decompensated chronic heart failure without cachexia

STUDY OBJECTIVE: To evaluate the clinical relevance of circulating tumor necrosis factor-alpha (TNF alpha) in subjects with advanced acutely decompensated congestive heart failure (CHF) and to determine the modulatory effect of clinical interventions on short-term elaboration of this cytokine. DESIGN: Prospective, case-controlled study. SETTING: Inpatient and outpatient (hospital and clinic), at regional academic medical center. PATIENT INTERVENTIONS: Plasma concentrations of TNF alpha were determined in 25 healthy, normal control subjects and in 29 noncachectic patients with advanced CHF (mean ejection fraction = 16 +/- 6%) who required hospitalization for i.v. diuretic and/or inotropic therapy despite optimization of oral medical regimens. CHF patients were divided into two groups: diuretic responsive (group A; n = 6) and diuretic resistant requiring inotropic support (group B; n = 23). Group B was randomly allocated to receive either i.v. dobutamine (n = 13) or milrinone (n = 10) for 72 h. TNF alpha levels in CHF patients were measured serially at baseline, at 6 h, at 48 h, at 72 h, and at 1-week follow-up after hospital discharge. RESULTS: Plasma TNF alpha levels at baseline in CHF patients were 4.0 +/- 1.1 pg/mL (range, 0.5 to 6.5 pg/ mL) and 2.5 +/- 0.6 pg/mL (range, 0.5 to 6.8 pg/mL) in groups A and B, respectively, which were significantly different (p < 0.002) from normal subjects (0.89 +/- 0.40 pg/mL; range, 0.5 to 9.7 pg/mL). Despite clinically successful therapy with i.v. diuretics, dobutamine, or milrinone, plasma levels of this cytokine remained unchanged. Plasma TNF alpha in CHF patients measured in recovery (1 week after hospital discharge) was 5.1 +/- 1.2 pg/mL (range, 1.0 to 9.9 pg/mL) and 3.9 +/- 0.8 pg/mL (range, 0.5 to 8.7 pg/mL) in groups A and B, respectively. CONCLUSION: These findings suggest that although noncachectic patients with chronic heart failure who suffer acute decompensation elaborate significantly higher circulating levels of TNF alpha compared with healthy control subjects, no significant reduction or alteration in circulating TNF alpha is noted in the short-term follow-up despite clinical improvement.     

Effect of early enalapril therapy on left ventricular function and structure in acute myocardial infarction

Infarct expansion starts within hours to days after transmural myocardial injury. Previous echocardiographic and left ventriculographic studies demonstrated that angiotensin-converting enzyme (ACE) inhibitor therapy limits left ventricular dilatation, particularly in patients with anterior wall acute myocardial infarction (AMI) or impaired left ventricular function. Forty-three patients with an acute Q-wave AMI were randomized within 24 hours of symptom onset to intravenous enalaprilat (1 mg) or placebo. Patients were then given corresponding oral therapy and followed for 1 month. Predrug and 1-month gated blood pool scans were obtained in 32 patients to evaluate changes in cardiac volumes and ejection fraction. Twenty-three patients underwent magnetic resonance imaging at 1 month to evaluate left ventricular infarct expansion. Blood pressure decreased at 6 hours but returned to baseline in both groups after 1 month of therapy. The change in cardiac volumes from baseline to 1 month differed between the placebo (end-diastolic volume +16 +/- 5 ml, end-systolic volume +8 +/- 6 ml), and enalapril (end-diastolic volume -8 +/- 9 ml and end-systolic volume -14 +/- 7 ml) groups (p < 0.05 vs placebo). Global and infarct zone ejection fractions improved significantly at 1 month in the enalapril group (+6 +/- 3% and 19 +/- 5%, respectively) but did not change over 1 month in the placebo group. Infarct segment length and infarct expansion index by magnetic resonance imaging were significantly less in those treated with enalapril, suggesting less infarct expansion in this group. Thus, early administration of enalaprilat to patients presenting with a first Q-wave AMI prevents cardiac dilatation and infarct expansion.     

NSAIDs associated with increased risk of congestive heart failure in elderly patients taking diuretics

BACKGROUND: Both diuretics and nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used, in particular among the elderly. The use of NSAIDs may decrease the efficacy of diuretics and induce congestive heart failure (CHF) in patients treated with diuretics. OBJECTIVE: To investigate the risk of CHF associated with combined use of diuretics and NSAIDs in patients older than 55 years. METHODS: We conducted a study in a base cohort of 10,519 recipients of diuretics and NSAIDs identified in the PHARMO database during the period from 1986 through 1992. The incidence density of hospitalizations for CHF during exposure to both diuretics and NSAIDs (index) was compared with that during exposure to diuretics only (reference). RESULTS: We found an overall increased risk of hospitalization for CHF during periods of concomitant use of diuretics and NSAIDs compared with use of diuretics only (crude relative risk, 2.2; 95% confidence interval, 1.7-2.9). After adjusting for cofactors including age, sex, history of hospitalization, and drug use, a 2-fold increased risk remained (relative risk, 1.8; 95% confidence interval, 1.4-2.4). CONCLUSION: Use of NSAIDs in elderly patients taking diuretics is associated with a 2-fold increased risk of hospitalization for CHF, especially in those with existing serious CHF.     

Angiotensin-converting enzyme inhibitor in the treatment of epirubicin-induced dilated cardiomyopathy

Anthracycline chemotherapy of cancer can cause severe, frequently fatal congestive heart failure (CHF), the first line treatment for which is diuretics and digoxin. We have studied the use of an ACE-inhibitor added as a third agent. Of 85 patients evaluable for cardiotoxicity after treatment with a median of 1000 mg/m2 of epirubicin for metastatic breast cancer, nine developed CHF at 1.5 to 13 months after therapy. Left ventricular ejection fraction decreased from normal to 18 to 35%. All patients received digitalo-diuretic therapy and after a transient clinical relief enalapril or ramipril increasing from 1.25 mg orally daily to 10-15 mg after 4-6 weeks. Eight of the nine patients deteriorated while on digitalo-diuretic therapy. Within three months of starting the ACE-inhibitor in these patients, LVEF increased to normal or near normal. Only one patient died in heart failure. Follow-up ranged from 11-42 months (median 26) and survival in the nine patients was similar to that of those who did not develop CHF. We suggest that treatment of anthracycline-induced CHF with an ACE-inhibitor should start within one to two weeks after digitalo-diuretic therapy regardless of the severity of symptoms rather than waiting for clinical deterioration.     

Use of digoxin, diuretics, beta blockers, angiotensin-converting enzyme inhibitors, and calcium channel blockers in older patients in an academic hospital-based geriatrics practice

OBJECTIVE: To investigate the prevalence of and indications for digoxin use and the prevalence of beta blocker and calcium channel blocker use in older patients with previous myocardial infarction or coronary artery disease (CAD), and the prevalence of use of diuretics, beta blockers, angiotensin-converting enzyme (ACE) inhibitors, and calcium channel blockers in older patients with hypertension in an academic hospital-based geriatrics practice. DESIGN: A retrospective analysis of charts from 528 unselected older patients, seen from June 1995 through July 1996 at an academic hospital-based geriatrics practice, was performed to investigate the prevalence of digoxin use and indications for digoxin use, the prevalence of beta blocker and calcium channel blocker use in older patients with previous myocardial infarction or coronary artery disease (CAD), and the prevalence of use of diuretics, beta blockers, angiotensin-converting enzyme (ACE) inhibitors, and calcium channel blockers in older patients with hypertension. SETTING: An academic hospital-based, primary care geriatrics practice staffed by fellows in a geriatrics training program and full-time faculty geriatricians. PATIENTS: A total of 416 women and 112 men, mean age 81 +/- 8 years (range 58 to 101), were included in the study. MEASUREMENTS AND MAIN RESULTS: Ninety-two of the 528 patients (17%) were taking digoxin. Recorded indications for digoxin were atrial fibrillation with or without congestive heart failure (CHF) in 39% of patients, CHF with sinus rhythm and abnormal left ventricular ejection fraction (LVEF) in 18% of patients, a clinical assessment of CHF with sinus rhythm and no recorded measurement of LVEF in 20% of patients, paroxysmal atrial fibrillation in 14% of patients, and coronary artery disease (CAD) in 9% of patients. Of 121 patients with previous myocardial infarction, 23 (19%) were prescribed beta blockers, and 54 (45%) were taking calcium channel blockers. Of 173 patients with CAD, 41 (24%) were treated with beta blockers, and 79 (46%) were taking calcium channel blockers. LVEF was not recorded in the charts of 90 of 121 patients (74%) with prior myocardial infarction and of 125 of 173 patients (72%) with CAD. Of 480 older patients with hypertension, 154 (37%) were treated with diuretics, 55 (13%) were treated with beta blockers, 160 (38%) were treated with ACE inhibitors, and 197 (47%) were treated with calcium channel blockers. CONCLUSIONS: In 528 older patients seen in an academic hospital-based geriatrics practice, the prevalence of digoxin use was 19%. Appropriate indications for digoxin were documented clearly in the charts of 53 of 92 patients (57%). Calcium channel blockers were used more often than beta blockers in patients with previous myocardial infarction or CAD. Calcium channel blockers were the most frequently used antihypertensive drugs.     

Early changes in plasma brain and atrial natriuretic peptides in premature infants: correlation with pulmonary arterial pressure

To define the change in plasma natriuretic peptides in newborns, we prospectively studied 10 premature infants. They were followed sequentially during the first week of extrauterine life by two-dimensional and pulsed Doppler echocardiography, and studied for atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). We estimated mean pulmonary arterial pressure (MPAP) and measured blood pressure on days 1, 2, 3, 5, 7, respectively. Plasma ANP levels were 81.7 +/- 11.4 pg/ml on day 1 and 67.9 +/- 6.0 pg/ml on day 7, respectively. Between day 2 and day 7, there was a fall in MPAP, i.e. from 37 +/- 4 mmHg to 22 +/- 2 mmHg (P < 0.01), which was associated with a significant decrease in plasma BNP (41.8 +/- 10.1 pg/ml on day 2 vs. 10.4 +/- 0.9 pg/ml on day 7, P < 0.01). There was a positive correlation between MPAP and plasma BNP level (r = 0.643, P < 0.0001), but there was no correlation between MPAP and plasma ANP level. These data suggest that the pattern of secretion of BNP is different from that of ANP and that BNP levels reflect the changes of pulmonary arterial pressure in the neonatal period in premature infants.