Prognostic evaluation of neurohumoral plasma levels before and during beta-blocker therapy in advanced left ventricular dysfunction.

OBJECTIVES: The study assessed the relative predictive potency of neurohumoral factors in patients with advanced left ventricular (LV) dysfunction during neurohumoral blocking therapy. BACKGROUND: The course of heart failure is characterized by progressive LV deterioration associated with an increase in cardiac (natriuretic peptides) and predominantly extracardiac (norepinephrine, big endothelin [big ET]) hormone plasma levels. METHODS: Plasma hormones were measured at baseline and months 3, 6, 12 and 24 in 91 patients with heart failure (left ventricular ejection fraction [LVEF] <25%) receiving 40 mg enalapril/day and double-blind atenolol (50 to 100 mg/day) or placebo. After the double-blind study phase, patients were followed up to four years. Stepwise multivariate regression analyses were performed with 10 variables (age, etiology, LVEF, symptom class, atenolol/placebo, norepinephrine, big ET, log aminoterminal atrial natriuretic peptide, log aminoterminal B-type natriuretic peptide [N-BNP] and log B-type natriuretic peptide [BNP]). During the study, the last values prior to patient death were used, and in survivors the last hormone level, New York Heart Association class and LVEF at month 24 were used. RESULTS: Thirty-one patients died from a cardiovascular cause during follow-up. At baseline, log BNP plasma level (x2 = 13.9, p = 0.0002), treatment allocation (x2 = 9.5, p = 0.002) and LVEF (x2 = 5.6, p = 0.017) were independently related to mortality. During the study, log BNP plasma level (x2 = 21.3, p = 0.0001) remained the strongest predictive marker, with LVEF (x2 = 11.2, p = 0.0008) log N-BNP plasma level (x2 = 8.9, p = 0.0027) and treatment allocation (x2 = 6.4, p = 0.0109) providing additional independent information. CONCLUSIONS: In patients with advanced LV dysfunction receiving high-dose angiotensin-converting enzyme inhibitors and beta-blocker therapy BNP and N-BNP plasma levels are both independently related to mortality. This observation highlights the importance of these hormones and implies that they will likely emerge as a very useful blood test for detection of the progression of heart failure, even in the face of neurohumoral blocking therapy.

Prognostic value of hemodynamic vs big endothelin measurements during long-term IV therapy in advanced heart failure patients.

STUDY OBJECTIVE: To compare hemodynamics and plasma big endothelin levels in patients awaiting heart transplantation who are receiving continuous IV therapy, and to establish their respective potency for predicting future cardiac events. DESIGN: A randomized, prospective trial of ambulatory continuous treatment with IV prostaglandin E(1) (PGE(1)) vs dobutamine. A subanalysis was conducted of all patients who completed 4 weeks of follow-up in regard to treatment effects on hemodynamics and big endothelin plasma levels. PATIENTS: Thirty-two listed heart transplant candidates who were refractory to oral treatment, 21 patients who were receiving PGE(1), and 11 patients receiving dobutamine. MEASUREMENTS AND RESULTS: Hemodynamics and plasma big endothelin levels were measured at baseline and after 4 weeks. The cardiac index increased significantly (PGE(1) group, 1.7 +/- 0.4 vs 2.5 +/- 0.6 L/min/m(2); dobutamine group, 1.8 +/- 0.3 vs 2.3 +/- 0.6 L/min/m(2); p < 0.05), whereas the systemic vascular resistance index (SVRI) decreased significantly only in the PGE(1) group (3,352 +/- 954 vs 2,178 +/- 519 dyne. s. cm(-5)/m(2); p < 0. 05). The plasma big endothelin level decreased significantly (PGE(1) group, 7.6 +/- 3.1 vs 4.7 +/- 2.6 fmol/mL; dobutamine group, 6.5 +/- 3.7 vs 5.0 +/- 2.6 fmol/mL; p < 0.01 for the time effect). Plasma big endothelin (beta = 0.393; chi(2) = 10.8; p = 0.001) and SVRI (beta = 0.003; chi(2) = 6.9; p < 0.01), both measured after 4 weeks of continuous treatment, were the only independent predictors of future outcome. CONCLUSION: Continuous treatment over 4 weeks with either PGE(1) or dobutamine in patients awaiting heart transplantation yields an improved hemodynamic state accompanied by a reduction of increased big endothelin levels. Plasma big endothelin measured after 4 weeks of continuous therapy provides prognostic information about future outcome.

Enzyme immunoassays for fragments (epitopes) of human proatrial natriuretic peptides.

Several peptides derived from the N-terminal sequence of pro-atrial natriuretic peptide (proANP) have been tested successfully as markers of heart disease. We have developed specific and sensitive competitive enzyme immunoassays for fragments [1-30] and [31-67] of proANP. Antisera were raised in sheep against synthetic peptides predicted to be highly immunogenic. Binding specificity was determined by epitope mapping. Microtiter plates were coated with antibody specific for the Fc region of sheep IgG to capture the affinity-purified specific anti-proANP antibodies in an oriented and reproducible form. Synthetic proANP calibrators or diluted samples were incubated simultaneously with biotinylated peptide and binding was quantitated using streptavidin-peroxidase and TMB. Immunoreactive proANP could be measured in diluted plasma, serum and urine. The detection limits of the proANP[1-30] and proANP[31-67] assays were 2.5 and 10 pmol/l respectively. The linearity of samples diluted beyond the recommended assay conditions was good. Recoveries of added standard peptides ranged from 102 to 112%. Circulating concentrations of immunoreactive proANP in 115 healthy subjects ranged from 0.11 to 0.47 nmol/l proANP[1-30] and 0.18 to 0.79 nmol/l proANP[31-67]. In patients with cardiac disease, proANP levels were increased significantly. The reference interval of proANP[31-67] in urine was 0.09 to 1.7 nmol/l, several-fold higher than proANP[1-30] (

Effects of prostaglandin E1, dobutamine and placebo on hemodynamic, renal and neurohumoral variables in patients with advanced heart failure.

Excessive neurohumoral activity remains a major burden to the circulation of patients with advanced heart failure. Prostaglandin E1 (PGE1), a balanced i.v. vasodilator, was shown to elicit favorable hemodynamic and clinical effects in this cohort. A prospective randomized parallel group trial was performed to evaluate acute, intermediate and chronic changes in hemodynamic, neurohumoral and renal variables in response to PGE1, dobutamine and placebo. Thirty patients with class III and IV heart failure and low cardiac index (mean 1.9 l/min/m2) two hours after oral drugs including high dose enalapril were included. A 7-day-infusion of PGE1 (16.5 +/- 5 ng/kg/min, range 10 to 20 ng/kg/min, group A n = 10), dobutamine (4.5 +/- 1 micrograms/kg/min, range 2.5 to 5 micrograms/kg/min, group B n = 10) or placebo (saline, group C n = 10) was administered via a central venous access line after stepwise titration until intolerable side effects developed with PGE1 or a 20% increase in cardiac index occurred with dobutamine, which was continued on this dose throughout while PGE1 was maintained on 50% peak dose. Hemodynamic data were collected at baseline, at peak dosages, after 12 hours and after 7 days. Of neurohumoral variables plasma norepinephrine, big endothelin (Big ET) and atrial natriuretic peptide (ANP) were simultaneously evaluated using RIA methods. Renal plasma flow (by paraaminohippurate clearance) and glomerular filtration rate (by iothalamate clearance) was measured prior to and during the infusions (after 12 hours and after 7 days). At peak dose and at 12 hours significant drops from baseline of mean pulmonary artery pressure, pulmonary capillary wedge pressure and systemic vascular resistance were observed which were accompanied by a rise in cardiac output with both PGE1 and dobutamine. These changes were maintained through 7 days when pulmonary vascular resistance levels also fell with both active drugs. Blood pressure did not change throughout, but PGE1 increased heart rate slightly at 12 hrs. Both PGE1 and dobutamine enhanced renal plasma flow after 7 days, but only PGE1 decreased glomerular filtration fraction significantly. Glomerular filtration rate did not change with either drug. PGE1 decreased ANP levels at 12 hrs, and dobutamine increased big ET levels at peak, but decreased big ET at 7 days. Norepinephrine levels were unaffected throughout. Except a slight decrease in right atrial pressure after 7 days placebo did not change any measured variable significantly. Taken together, these data suggest that treatment with PGE1 is as efficacious as low-dose dobutamine in improving cardiac performance and renal perfusion in advanced heart failure. Of importance, no deleterious neurohumoral counterregulation was observed with PGE1.

Hemodynamic and neurohumoral effects of long-term prostaglandin E1 infusions in outpatients with severe congestive heart failure.

BACKGROUND: Prostaglandins of the E type are potent endogenous vasodilators that also interfere with the activity of the sympathetic nervous system. Thus treating patients with end-stage heart failure with prostaglandin E1 (PGE1) infusions seems to accord well with the hypothesis that neurohumoral imbalance rather than hemodynamic derangements should be the priority in the treatment of heart failure. METHODS: We sought to investigate neurohumoral in addition to hemodynamic changes during long-term PGE1 infusion and determined plasma renin activity, atrial natriuretic peptide, norepinephrine, and big endothelin plasma levels in 13 male patients with heart failure whose symptoms remained severe in spite of optimized oral therapy with digitalis, nitrates, furosemide (185 +/- 72 mg/d) and enalapril (33 +/- 3 mg/d). PGE1 infusion rate was started with 2.5 ng/kg/min and stepwise increased to the maximum tolerated dose (26 +/- 4 ng/kg/min), which was halved for continuous infusion through the following 12 hours and further stepwise reduced to an average dose of 8 +/- 1 ng/kg/min. Right heart catheterization was performed for acute hemodynamic studies and after 4 weeks. All patients were discharged with a catheter that was connected to a portable pump for home therapy. RESULTS: Acute effects of PGE1 were reductions in systemic blood pressure, (p < 0.05), right atrial pressure (p < 0.001), pulmonary artery pressure (p < 0.05), pulmonary capillary wedge pressure (p < 0.01), systemic and pulmonary vascular resistance index (both p < 0.01) and an increase in cardiac and stroke volume index (both p < 0.001) without a change in heart rate. After 4 weeks a persistent increase from baseline in cardiac index (from 1.9 +/- 0.1 to 2.5 +/- 0.2 L/min/m2; p < 0.01) and in pulmonary vascular resistance index (from 479 +/- 50 to 331 +/- 29 dynes x sec/cm5 x m2; p < 0.05) was observed. Atrial natriuretic peptide (p < 0.05) decreased, and norepinephrine and big endothelin showed a tendency to a lower level. Concomitantly, New York Heart Association functional class changed (p = 0.0001), with one patient's condition remaining class IV, the conditions of seven patients decreasing to class II, and the conditions of five patients decreasing to class III. CONCLUSION: Thus long-term parenteral home therapy with PGE1 infusions in patients with severe end-stage heart failure elicited beneficial clinical and hemodynamic effects without activating neurohumoral counterregulatory systems.

Effects of two different enalapril dosages on clinical, haemodynamic and neurohumoral response of patients with severe congestive heart failure.

Angiotensin converting enzyme inhibitors improve symptoms and prolong life in congestive heart failure, but the dose in the individual patient is uncertain. A randomized, 48-week, double-blind study was performed to investigate the safety and efficacy of 'high' in comparison to continued 'low' angiotensin converting enzyme inhibitor therapy in severe heart failure. Eighty-three patients (56 +/- 1.1 years; 69 men, 14 women) in New York Heart Association functional class III/IV on digoxin, furosemide and 'low' angiotensin converting enzyme inhibitors (captopril < or = 50 mg.day-1 or enalapril < or = 10 mg.day-1) were included. After a > or = 14 day run-in on 10 mg.day-1 enalapril, digitalis and furosemide, right heart catheterization at rest and exercise was performed. All patients presented with atrial pressure > 10 mmHg and/or pulmonary artery pressure > 35 mmHg, and/or cardiac index < 2.5 l.min-1.m-2 at rest. Patients then received enalapril 5 mg twice daily (n = 42), or 20 mg twice daily (n = 41) in random order. Thus, patients randomized to low doses of enalapril actually had no change in therapy from baseline to 48 weeks. Forty-three patients (52%) completed the study, 19 patients on the low dose and 24 patients on the high dose. Both dosages equally influenced survival with 15 (18%) deaths, eight on low dose and seven on high dose. After 48 weeks, functional capacity by New York Heart Association class improved more on the high dose than on the low dose (P = 0.04). In contrast, alterations in invasive haemodynamic variables at rest and exercise as well as maximal exercise capacity were comparable in both groups. Diastolic blood pressure decreased and the change between both groups was statistically significant (P = 0.01). Changes in plasma creatinine levels did not differ between high and low dose treatment and no patients had to be withdrawn because of deterioration in kidney function. With regard to neurohumoral activity, a tendency to a discrepant response to both treatments was observed with a blunted increase in noradrenaline on high versus low enalapril dose. Thus, high-dose enalapril treatment proved superior to low dose as regards symptomatology in severe heart failure after long-term treatment, despite similar effects on haemodynamics and on maximal exercise capacity.

Prognostic impact of big endothelin-1 plasma concentrations compared with invasive hemodynamic evaluation in severe heart failure.

OBJECTIVES: This study sought to test the hypothesis that big endothelin-1 plasma levels in advanced heart failure are related to survival. BACKGROUND: In heart failure, production of the potent vasoconstrictor endothelin-1 is increased. Because elevation of immunoreactive endothelin-1 in severe heart failure is primarily related to the precursor "big" endothelin-1, increased big endothelin-1 levels may be associated with a poor prognosis. METHODS: Plasma big endothelin-1 concentrations, in addition to 16 clinical, hemodynamic and neurohumoral variables, were obtained from 113 patients (mean age -=/[SEM] 53 +/- 1 years) with left ventricular ejection fraction <20% and were related to 1-year mortality by a stepwise Cox regression multivariate analysis. RESULTS: Plasma big endothelin-1 concentrations were significantly higher in patients with moderate and severe heart failure than in those with mild heart failure (4.5 +/- 0.4 and 6.0 +/- 0.1 vs. 2.7 +/- 0.1 fmol/ml, p = 0.0001, respectively) and lower in 58 one-year survivors than in 29 nonsurvivors (2.6 +/- 0.1 vs. 5.9 +/- .04 fmol/ml, p = 0.0001) and 26 heart transplant recipients. By univariate analysis, big endothelin-1 plasma concentrations (p < 0.0001), functional class, daily furosemide dose, left ventricular ejection fraction, most hemodynamic variables and plasma atrial natriuretic peptide, sodium renin activity and aldosterone levels were all related to mortality, but only functional class provided additional prognostic information when big endothelin-1 plasma levels were entered into the multivariate model. CONCLUSIONS: In advanced heart failure, plasma big endothelin-1 is strongly related to survival and appears to predict 1-year mortality better than hemodynamic variables and levels of atrial natriuretic peptide, an established neurohumoral prognostic marker in chronic heart failure.

Increased levels of circulating islet amyloid polypeptide in patients with chronic renal failure have no effect on insulin secretion.

To elucidate the metabolism of islet amyloid polypeptide (IAPP) with respect to a possible renal elimination we investigated IAPP levels in 20 lean, nondiabetic patients with renal failure maintained on chronic hemodialysis (HD) and in 20 healthy controls. The basal levels of IAPP were significantly higher in uremic patients than in controls (15.1 +/- 3.2 vs. 3.2 +/- 0.2 pM, P < 0.001) suggesting renal excretion of IAPP. To investigate the impact of chronically elevated levels of endogenous IAPP on insulin secretion and insulin sensitivity, a frequently sampled intravenous glucose tolerance test (FSIGT) was performed in a subset of patients on hemodialysis and in age-matched healthy controls (C) and obese patients with normal (NGT) and with impaired glucose tolerance (IGT). Insulin sensitivity index (SI) was 8.7 +/- 1.5 in C (P < 0.05 vs. NGT, P < 0.01 vs. IGT), 5.4 +/- 0.9 in HD (P < 0.05 vs. IGT), 3.1 +/- 1.0 in NGT, and 2.0 +/- 0.5 in IGT. First phase insulin secretion was increased in patients on HD compared with those of several control groups. The results of this study therefore indicate a renal route of metabolism of IAPP. Increased endogenous circulating IAPP levels over a long period of time do not lead to a decrease in insulin release in patients on HD and do not cause the insulin resistance commonly seen in obesity and diabetes. Increased levels of circulating IAPP therefore are not likely to be a pathogenetic factor in the development of non-insulin-dependent diabetes mellitus (NIDDM).

Pattern of endothelin immunostaining during rejection episodes after kidney transplantation.

A pathophysiological role for endothelin (ET), one of the most potent vasoconstrictor peptides, has been suggested in ATN and during kidney allograft rejection. As ET is known to have predominantly local effects, we investigated intrarenal ET content in 82 kidney transplant biopsies and 10 normal control kidneys. ET-immunostaining, using a polyclonal anti-ET-1 antibody was investigated in 4 intrarenal vascular beds (glomeruli, capillaries, arterioles, arteries) and in tubular epithelium. Normal kidneys showed a strong staining of endothelial cells in all vessels and of tubular epithelium. In biopsies with signs for acute vascular rejection a marked decrease in ET staining intensity was seen. In contrast, normal staining similar to control kidneys was detected in interstitial rejection and in ATN. The presence of chronic CyA toxicity, however, lead to a significant reduction of endothelial ET staining. Neither mean doses nor trough levels of CyA correlated closely with the immunostaining findings. Plasma big-ET levels were elevated during vascular rejection, but not in interstitial rejection and ATN. This study demonstrates a significant reduction of ET immunostaining in intrarenal vascular endothelium of kidney transplant biopsies showing signs of endothelial damage. In vascular allograft rejection these changes are often associated with a concomitant rise in plasma ET levels. Our findings support a postulated role of ET in vascular rejection and during CyA toxicity and show that endothelial damage, independent of its genesis, can lead to a reduction of intrarenal ET content.

Aerobic fitness and sympatho-adrenal response to short-term psycho-emotional stress under field conditions.

A possible relationship between aerobic fitness (AF), measured by maximal cycle ergometry (CE) and sympatho-adrenal response to acute, short lasting psycho-emotional stress was investigated by monitoring heart rate (fc) and excretion of catecholamines. The activation of the sympatho-adrenal system was characterised by the noradrenaline: adrenaline ratio. A group of 11 healthy men [22.8 (SD 2.52) years] lived under identical environmental conditions; their mean maximal oxygen uptake (VO2max) was 47.1 (SD 3.9) ml.min-1.kg-1. After the physiological and psychological laboratory tests had been completed the fc of the subjects was monitored continuously during the "guerilla slide" and "parachute jump by night", two emotionally stressful military tasks. Maximal fc (fc, max) attained during these events was 84.5% and 83% of fc, max during CE (fc, max, CE), respectively. A significant relationship (r = -0.92, P < 0.0002) between fc, max reached during the stressful tasks and VO2max was found only for the guerilla slide, which was preceded by physical strain, sleep deprivation and energy deficit. One subject with some prior experience in parachuting showed the lowest fc response and the lowest sympatho-adrenal activation in both events, independent of the degree of AF. In conclusion, AF was found to influence the sympatho-adrenal and fc response to acute, short-lasting emotional stress when the stressful event was aggravated by preceding physical strain, the magnitude of the stress response depending largely on individual experience and effective mechanisms for coping with specific stimuli.

Plasma big endothelin-1 concentrations in congestive heart failure patients with or without systemic hypertension.

Plasma endothelin concentrations were evaluated in 53 chronic, congestive heart failure (CHF) patients with or without history of systemic hypertension, as well as in 9 with hypertension only and in 22 healthy control subjects. Plasma renin, aldosterone and atrial natriuretic peptide, as well as clinical and hemodynamic data were determined. In patients with CHF, big endothelin-1 was, independent of hypertension history, significantly greater than in hypertensive patients with normal cardiac function and in control subjects (both p < 0.0001). Patients with severe CHF had significantly greater big endothelin-1 values than did those with moderate CHF. During 12-month follow-up, 11 patients with CHF underwent heart transplantation, and 9 died; these patients had significantly greater big endothelin-1 concentrations than did the 33 clinically stable patients (p < 0.001). Big endothelin-1 and atrial natriuretic peptide correlated with right atrial pressure, pulmonary capillary wedge pressure, left ventricular ejection fraction, effort capacity and severity of CHF (New York Heart Association functional class).

Effect of dexamethasone on insulin sensitivity, islet amyloid polypeptide and insulin secretion in humans.

The response of islet amyloid polypeptide and insulin and their molar ratios were investigated in eight healthy volunteers before and after treatment with dexamethasone by oral and frequently-sampled intravenous glucose tolerance tests. Following dexamethasone treatment the insulin sensitivity index decreased significantly from 6.5 +/- 1.3 to 4.1 +/- 1.0 (microU.ml-1).min-1, p < 0.05. The area under the curve representing above-basal levels of insulin during oral glucose tolerance test increased significantly following dexamethasone treatment from 48132 +/- 9736 to 82230 +/- 14846 pmol.l-1 x 3 h-1, p < 0.05, the area under the curve of islet amyloid polypeptide increased from 1308 +/- 183 to 2448 +/- 501 pmol.l-1 x 3 h-1, p < 0.05. The overall insulin/islet amyloid polypeptide molar ratios calculated from the area under the curve during the 3-h period of the oral glucose tolerance test was not significantly different before and after dexamethasone treatment (42 +/- 5 vs 40 +/- 4). During the oral glucose tolerance test the insulin/islet amyloid polypeptide ratio increased significantly from baseline to 30 min (p < 0.05), then declined towards initial values before and after dexamethasone treatment. In conclusion, dexamethasone induced a significant decrease in insulin sensitivity and a significant increase in insulin secretion during the oral glucose tolerance test. However, in contrast to previous animal experiments we did not find a change in the insulin/islet amyloid polypeptide ratio before and after dexamethasone treatment.

Construction and use of two alpha-human atrial natriuretic peptide-fragment affinity chromatography columns in the isolation of C- and N-terminal epitope-specific antibodies for use in a prototype alpha-hANP biosensor.

Two alpha-human atrial natriuretic peptide (alpha-hANP) based affinity chromatography columns were produced by covalently immobilizing the C- and N-terminal epitopes of alpha-hANP. The stationary phase was made from a controlled-pore-glass bead solid support, which was silanized and treated with sulphosuccinimidyl 4-(maleimidomethyl)cyclohexyl carboxylate before the individual fragments were immobilized by substitution at their thiol groups. These columns were used to isolate alpha-hANP-specific antibodies from a goat anti-alpha-hANP serum, which were then further sorted according to their epitope specifity. These C- and N-terminal epitope-specific antibodies were in turn used as components in the construction of an alpha-hANP biosensor based on an enzyme-linked immunosorbent assay (ELISA) sandwich principle. Initial in vitro testing of the sensor using a physiological alpha-hANP solution showed a reproducible response to the peptide. There is to date no other equally fast, sensitive and precise method available to detect this peptide. This alpha-hANP sensor may prove to be an invaluable aid in human medicine as a monitor of patient status during transplant surgery, for example, an area inaccessible to radioimmunoassay and normal ELISA techniques.

Increased levels of plasma amylin in advanced renal failure.

Amylin, a 37 amino acid polypeptide, has been suggested to play a prominent role in the pathogenesis of insulin resistance in type II diabetes mellitus. Various studies have demonstrated most recently that amylin is cosecreted with insulin. No data are available on the elimination of amylin from the circulation. We therefore tested plasma levels of amylin, insulin and C-peptide in 49 non-obese, non-diabetic patients (27 male/22 female) with various degree of renal impairment (Group A: CCr less than 20 ml/min, n = 20; Group B: CCr 20-89 ml/min, n = 18; and Group C: CCr greater than 80 ml/min, n = 9). We found a significant increase of plasma amylin when kidney function, expressed by creatinine clearance fell below 20 ml/min (17.9 +/- 1.7 vs. 12.2 +/- 0.8 vs. 8.8 +/- 1.2 pg/ml; p = 0.0005). Plasma amylin correlated closely with serum C-peptide (r = .764; p = 0.0001), and to a lesser extent with insulin (r = .595; p = 0.0001) underlining its postulated cosecretion with these peptides. The data indicate that amylin might be eliminated by renal mechanisms. Our data show that besides type II diabetes mellitus, advanced renal failure is another clinical situation with enhanced plasma amylin levels. Whether amylin plays any pathogenetic role in renal patients remains to be elucidated.

[Effects of treatment of arrhythmias requiring therapy in dilated cardiomyopathy with amiodarone on alpha human atrial natriuretic peptide]. / Auswirkungen der Behandlung therapiepflichtiger Arrhythmien bei dilatativer CMP mit Amiodaron auf das alpha-humane atriale natriuretische Peptid (alpha-hANP).

In a longitudinal study comprising a total of 18 patients, the paradoxical time course of hANP plasma levels, i.e. the reproducibility of the low levels previously reported in cases of extreme cardiac insufficiency after administration of amiodarone, was investigated over a period of 9 months. At the same time, the effect of the degree of cardiac insufficiency and arrhythmia on the secretion of hANP was observed. The patients had been admitted to hospital because of the diagnoses "cardiac insufficiency secondary to cardiomyopathy" or "Grade IVb arrhythmia according to Lown's classification". During in-patient treatment, antiarrhythmic therapy was commenced in all patients. Clinical examinations and determinations of humoral parameters during therapy showed a substantial number of patients, who exhibited no increase in hANP levels despite massive cardiac decompensation. As far as drug therapy of patients with severe arrhythmias secondary to congestive (dilated) cardiomyopathy is concerned, amiodarone has proved to be the drug of choice in combination with digitalis, ACE inhibitors and diuretics. There is a close correlation between the degree of cardiac insufficiency and plasma hANP levels.

Decrease of stimulated amylin release precedes impairment of insulin secretion in type II diabetes.

Amylin, a 37-amino acid polypeptide, has been identified as the major protein component of pancreatic amyloid deposits in patients with non-insulin-dependent (type II) diabetes mellitus. Amylin is stored and released together with insulin and has been proposed to play a major role in the pathogenesis of type II diabetes. To compare amylin release and its proportion to insulin secretion under different metabolic conditions, oral and intravenous glucose tolerance tests (OGTT and IVGTT, respectively) were performed in healthy, lean control subjects, obese patients with normal and impaired glucose tolerance (NGT and IGT, respectively), and obese type II diabetic patients. Compared with control subjects, basal and stimulated amylin secretion during OGTT was significantly higher in obese patients with NGT and IGT but not in type II diabetic patients. The integrated amylin response was significantly higher in obese patients with NGT than lean control subjects and type II diabetic patients matched for degree of obesity. The amylin-insulin ratio decreased slightly in obese subjects with NGT and IGT and significantly in type II diabetic patients. Amylin secretion was significantly stimulated during IVGTT in control subjects and obese patients with NGT and IGT but not in type II diabetic patients. These findings suggest that amylin is physiologically released by pancreatic beta-cells in a constant ratio to insulin in nondiabetic subjects. Glucose-stimulated amylin secretion is increased in obese subjects with NGT and IGT. In type II diabetes mellitus, amylin secretion relative to that of insulin is decreased, and amylin is not stimulated by IVGTT.

Radioimmunoassay of immunoreactive C-terminal big-endothelin(22-38).

Endothelin, a potent endogenous vaso-constrictor, is derived from its biosynthetic precursor by proteolytic degradation. The last step cleaves big-endothelin(1-38) to endothelin(1-21) and a C-terminal fragment. We have developed a radioimmunoassay for this peptide, based on an antiserum recognizing the C-terminal sequence big-endothelin(22-38) and cross-reacting with intact big-endothelin. To test for the presence of immunoreactive big-endothelin(22-38) in plasma, samples were extracted by passage through C18 silica cartridges, and desorption with methanol/water volume fraction 0.8. The yields of this purification and concentration procedure were about 70%. In 15 healthy persons we found concentrations of 1-11 pmol/l, which is about 10-fold higher than the reference levels reported for endothelin(1-21) or big-endothelin(1-38). Thus, endothelin-derived peptides containing the big-endothelin(22-38) sequence, but different from intact big-endothelin, do circulate in human blood. If a sufficiently tight correlation to levels of circulating endothelin(2-21) can be proven, this would facilitate studies on the physiological role of endogenous endothelin.