Biomedical subjects

Richard Pacher

Publications and source records attributed to Richard Pacher.

At least 19 recordsLinked to original sources

PubMed2006

Heart transplantation provides long-term survival benefit in stable patients experiencing heart failure without reverse left ventricular remodeling.

BACKGROUND: Heart transplantation does not provide short-term survival benefit in stable patients experiencing chronic heart failure (CHF) with optimized medical therapy. This study compared the outcome of stable patients with CHF with patients after heart transplantation in the long-term. METHODS: Between January 1995 and September 1997, 318 potential transplant candidates (New York Heart Association class III or IV, left ventricular ejection fraction [LVEF] <35%) were evaluated. After three months of therapeutic optimization, 108 patients were stable outpatients with maximally uptitrated neurohormonal antagonists. Seventy of the 318 patients underwent transplantation between January 1995 and December 1997. RESULTS: After an observation period of 7 to 10 years, stable patients with CHF had a significantly lower survival compared with transplanted patients (hazard ratio, 0.90; 95% confidence interval, 0.83-0.98; P=0.01). One-year LVEF (> or =30%) was the best independent predictor of long-term survival. Patients with an LVEF > or =30% had a similar survival; patients with an LVEF <30% had a significantly lower survival (hazard ratio, 0.82; 95% confidence interval, 0.75-0.90; P<0.001) compared with transplanted patients. CONCLUSION: Not in the short term (1.5 years) but in the long term (7-10 years), heart transplantation seems to provide survival benefit in stable patients with CHF except in patients with improved LVEF (> or =30%) after medical optimization.

Female↗

PubMed2006

Levosimendan and prostaglandin E1 for uptitration of beta-blockade in patients with refractory, advanced chronic heart failure.

BACKGROUND: In advanced chronic heart failure (CHF) 20% of patients do not tolerate beta-blockers and 50% do not reach target doses. AIM: To test whether levosimendan or prostaglandin E1 (PGE1) can facilitate uptitration of beta-blockers in advanced CHF. METHODS AND RESULTS: Seventy-five advanced CHF patients (LVEF<35%, NYHA class IIIb or IV) intolerant to beta-blocker uptitration to target doses (10 mg bisoprolol/day) were randomised to a monthly 24 h infusion with levosimendan (n=39) or a chronic infusion with PGE1 (n=36) for 3 months. Bisoprolol was uptitrated following predefined criteria. At 12 weeks, bisoprolol dose increased from 4 mg to 10 mg in both groups. Heart failure worsening occurred in 29 levosimendan patients (74%) versus 16 PGE1 patients (44%, p=0.008). Uptitration was impossible in 9 levosimendan patients (23%) versus 2 PGE1 patients (6%, p=0.03). The combined endpoint of death or urgent heart transplantation or implantation of a ventricular assist device was reached by 12 levosimendan patients (31%) versus 4 PGE1 patients (11%, p=0.04). After 1 year, LVEF increased from 23+/-7% to 28+/-11% (p=0.0004), and BNP decreased from 994+/-806 to 659+/-564 pg/ml (p=0.03). CONCLUSION: Levosimendan and PGE1 facilitate uptitration of beta-blockers in previously intolerant CHF patients. PGE1 treatment allowed uptitration in more patients and resulted in a better clinical outcome compared to levosimendan. This approach increased LVEF and decreased BNP after 1 year.

Adrenergic beta-Antagonists↗

PubMed2006

Midregional pro-A-type natriuretic peptide measurements for diagnosis of acute destabilized heart failure in short-of-breath patients: comparison with B-type natriuretic peptide (BNP) and amino-terminal proBNP.

BACKGROUND: The aim of the present study was to assess the utility of amino-terminal pro-A-type natriuretic peptide (NT-proANP) measurements for the emergency diagnosis of acute destabilized heart failure (HF), using a novel sandwich immunoassay covering midregional epitopes (MR-proANP). METHODS: The retrospective analysis comprised 251 consecutive patients presenting to the emergency department of a tertiary care hospital with dyspnea as a chief complaint. The diagnosis of acute destabilized HF was based on the Framingham score for HF plus echocardiographic evidence of systolic or diastolic dysfunction. A commercially available immunoluminometric assay was used for measurement of MR-proANP plasma concentrations. RESULTS: Median MR-proANP plasma concentrations were significantly higher in patients with dyspnea attributable to acute destabilized HF (338 pmol/L; n = 137) than in patients with dyspnea attributable to other reasons (98 pmol/L; n = 114; P <0.001). The area under the curve for MR-proANP was 0.876 (SE = 0.022; 95% confidence interval, 0.829-0.914), and the cutoff concentration with the highest diagnostic accuracy was 169 pmol/L (sensitivity, 89%; specificity, 76%; diagnostic accuracy, 83%). In the setting evaluated, diagnostic information obtained by MR-proANP measurements was similar to that obtained with B-type natriuretic peptide (BNP) and amino-terminal proBNP (NT-proBNP) measurements. CONCLUSIONS: MR-proANP measurements may be useful as an aid in the diagnosis of acute destabilized HF in short-of-breath patients presenting to an emergency department. The diagnostic value of MR-proANP appears to be comparable to that of BNP and NT-proBNP.

Acute Disease↗

PubMed2006

B-type natriuretic peptide and amino terminal proBNP predict one-year mortality in short of breath patients independently of the baseline diagnosis of acute destabilized heart failure.

BACKGROUND: The aim of the present study was to demonstrate the capability of B-type natriuretic peptide (BNP) and amino terminal proBNP (NT-proBNP) as prognostic markers in patients with dyspnoea as a chief complaint. METHODS: BNP and NT-proBNP plasma concentrations were obtained from 251 short of breath patients presenting to the emergency department of a tertiary care hospital. Patients with acute coronary syndromes or trauma were excluded. The endpoint was defined as all-cause mortality, and the study participants were followed up for 365 days from the time they attended the emergency department. RESULTS: Of the 251 patients, 62 died and 189 stayed alive during follow-up. In the present study, optimal cut off levels for the prediction of survival were 454 ng/L for BNP, and 2060 ng/L for NT-proBNP. Mortality was higher in patients with baseline BNP and NT-proBNP concentrations above these cut off levels (log rank p<0.001; hazard ratios, 0.325 and 0.357, respectively). In multivariate Cox proportional-hazards regression analyses, elevated BNP/NT-proBNP, low systolic blood pressure, and renal dysfunction were predictors of mortality even when the baseline diagnosis of acute destabilized heart failure was factored into the model. CONCLUSIONS: Both BNP and NT-proBNP measures obtained from short of breath patients presenting to an emergency department may be predictive of one-year all-cause mortality independently of the baseline diagnosis of acute destabilized heart failure.

Acute Disease↗

PubMed2005

Big endothelin-1 is not a predictor in aortic stenosis, but is related to arterial blood pressure.

BACKGROUND: In aortic stenosis, natriuretic peptides have recently been shown to correlate with ventricular function and to predict symptom-free survival and outcome. Elevated big endothelin-1 (bigET) is associated with poor prognosis in chronic heart failure, but little is known about its role in severe aortic stenosis. METHODS: In 61 patients with aortic stenosis (71+/-10 years, mean gradient 65+/-20 mm Hg, valve area 0.63+/-0.15 cm2), plasma bigET was determined by radioimmunoassay and related to echocardiographic parameters, symptoms and survival. Patients were followed for 1 year. RESULTS: BigET (mean 2.3+/-1.5, range 0.1-7.5 fmol/ml) was elevated > or = 1.9 fmol/ml in 54% of patients, but was not correlated to the transvalvular gradients or valve area. BigET did not differ significantly between 14 asymptomatic (2.4+/-1.0 fmol/ml) and 47 symptomatic patients (2.3+/-1.6 fmol/ml), although the highest levels were observed in 5 patients in NYHA class III-IV (4.2+/-2.2 fmol/ml, p=0.035). No significant difference in bigET was observed between 51 survivors and 10 patients who died during follow-up (2.2+/-1.4 vs 2.7+/-1.6 fmol/ml). BigET did not differ between 7 asymptomatic patients developing symptoms and those remaining asymptomatic during follow-up. BigET was significantly related to the systolic blood pressure and left ventricular systolic pressure (r=0.389, p=0.0025 and r=0.401, p=0.0018, respectively), but not to the diastolic blood pressure or interventricular septal wall thickness. BigET was inversely related to the left ventricular ejection fraction (r=0.327, p=0.01) and fractional shortening (r=0.391, p=0.044). CONCLUSION: Although frequently elevated, bigET-1 is not a useful predictor of symptoms or outcome in patients with severe aortic stenosis. BigET increases inversely with left ventricular function and directly with systolic left ventricular and blood pressure, but is not related to transvalvular gradients or valve area.

Aged↗

PubMed2005

Comparison of soluble glycoprotein 130 and cardiac natriuretic peptides as long-term predictors of heart failure progression.

BACKGROUND: In patients with heart failure, B-type natriuretic peptides (BNP, N-BNP) and atrial natriuretic peptide (ANP) are established prognostic markers. However, circulating interleukin (IL)-6-related cytokines and soluble glycoprotein 130 (sgp130), their common subunit for signal transduction, are also increased. We hypothesized that levels of circulating sgp130 and cardiac peptides provide independent prediction of worsening pump failure in the long term. METHODS: A series of 76 patients (77% male, 54 ischemic and 17 nonischemic, left ventricular ejection fraction 22% +/- 7%) had blood samples drawn for assay of sgp130, oncostatin-M, N-ANP, N-BNP, and BNP. A composite end point of worsening pump failure (requiring hospitalization, intravenous therapy, or urgent heart transplantation) and pump failure death was used for follow-up. RESULTS: During follow-up (up to 7 years), rate of worsening pump failure was 22.3%, including death. N-ANP (5666 +/- 3100 vs 7850 +/- 12164 fmol/ml), N-BNP (278 +/- 284 vs 250 +/- 297 pmol/ml), and oncostatin-M (15 +/- 28 vs 16 +/- 63 pg/ml) were similar in those who incurred worsening pump failure and in others. Mean sgp130 levels were 389 +/- 123 ng/ml in patients who developed worsening heart failure (Group A) and 289 +/- 123 ng/ml in stable patients (Group B; p < 0.0001). Mean BNP was 567 +/- 774 pg/ml in Group A and 307 +/- 324 pg/ml in Group B (p < 0.05). By using a cutoff value of 286 ng/ml for gp130 in Kaplan-Meier analysis, we found that the rate of freedom from worsening heart failure was significantly higher in patients below compared with patients above this cutoff point (p = 0.03). In univariate and multivariate Cox regression analysis, only sgp130 emerged as statistically significant (p < 0.001). CONCLUSIONS: In addition to BNP, sgp130 could be useful in identifying patients at high risk for heart failure progression.

Adult↗

PubMed2005

Flow-mediated vasodilation predicts outcome in patients with chronic heart failure: comparison with B-type natriuretic peptide.

OBJECTIVES: The aim of this study was to assess the predictive potency of impaired endothelium-dependent flow-mediated vasodilation (FMD) in patients with chronic heart failure (CHF). BACKGROUND: Chronic heart failure is associated with reduced FMD; the prognostic impact of this observation is unknown. METHODS: Seventy-five ambulatory CHF patients (United Network of Organ Sharing [UNOS] status 2) with a left ventricular ejection fraction (LVEF) < or =30%, despite optimized medical therapy (angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker, 100%; beta-blocker, 81%), were evaluated. Using high-resolution ultrasound, FMD of the brachial artery was assessed in addition to other neurohormonal, clinical, and hemodynamic variables. Age, gender, New York Heart Association (NYHA) functional class, LVEF, hemodynamic variables, B-type natriuretic peptide (BNP) levels, medical therapy, cardiovascular risk factors, and FMD were analyzed for prediction of the combined end point conversion to UNOS status 1 or death in a multivariate Cox model. RESULTS: Up to three years, 21 patients (28%) converted to UNOS status 1, and 6 patients (8%) died. Univariate risk factors for the combined end point were log BNP (p = 0.0032), FMD (p = 0.0033), NYHA functional class (p = 0.0132), beta-blocker therapy (p = 0.0367), and mean blood pressure (p = 0.0406). In the multivariate analysis, only FMD (p = 0.0007), log BNP (p = 0.0032), and mean blood pressure (p = 0.0475) were independently related to the combined end point. In the Kaplan-Meier plot, significantly more patients with FMD <6.8% (median) reached the combined end point, as compared with patients with FMD >6.8% (p = 0.004). CONCLUSIONS: In CHF, impaired FMD is a strong, independent predictor of conversion to UNOS status 1 or death.

Adult↗

PubMed2005

Short-term effects of levosimendan and prostaglandin E1 on hemodynamic parameters and B-type natriuretic peptide levels in patients with decompensated chronic heart failure.

BACKGROUND: Both levosimendan and prostaglandin E1 (PGE1) have beneficial effects on hemodynamic parameters and outcome compared to dobutamine in decompensated chronic heart failure (CHF). AIMS: We compared short-term effects of levosimendan versus PGE1 on hemodynamic parameters and B-type natriuretic peptide levels (BNP) in patients with decompensated CHF. METHODS AND RESULTS: 73 patients (cardiac index < 2.5 L/min/m2, pulmonary capillary wedge pressure (PCP) >15 mmHg) with decompensated CHF were randomised to treatment with either a 24 h-infusion of levosimendan (n=38) or a chronic infusion of PGE1 (n = 35). Hemodynamic parameters and BNP were measured at baseline, 24 and 48 h, BNP levels were also measured after 1 week. Baseline characteristics including concomitant medication were similar in both groups. Levosimendan and PGE1 increased cardiac output (CO) after 24 and 48 h. Levosimendan increased CO twice as much as PGE1 (24 h: Levosimendan +1.1 +/- 0.1 L/min, PGE1 +0.6 +/- 0.1 L/min, p < 0.001). Both drugs produced a comparable reduction in PCP and pulmonary artery pressure after 24 and 48 h. Levosimendan decreased BNP by 28% after 24 h and 22% after 48 h, but effects disappeared after 1 week. In contrast, PGE1 decreased BNP by 15% after 48 h (no change at 24 h), but a decrease of 20% was sustained at 1 week. CONCLUSIONS: The differential beneficial effects of levosimendan (greater increase in CO) and PGE1 (sustained decrease in BNP) may have a potential impact on clinical outcome.

Adolescent↗

PubMed2005

Influence of age and in-patient care on prescription rate and long-term outcome in chronic heart failure: a data-based substudy of the EuroHeart Failure Survey.

AIMS: To evaluate the prescription rate of neurohumoral drugs in chronic heart failure patients and the factors influencing prescription rates. Outcomes and their predisposing factors were also investigated. METHODS AND RESULTS: Of 1482 consecutive patients admitted to 3 Austrian hospitals participating in the EuroHeart Failure Survey, 341 were included in this data-based substudy. Follow-up time to evaluate outcome was up to 46 months. The prescription rates of renin-angiotensin (RAAS) antagonists and beta-blockers at the time of discharge were evaluated. The overall prescription rate and dosage were lower than the recommended levels. Hospitals with cardiac care had a significantly higher prescription rate than those without (p<0.001). Patients older than 75 years received significantly less therapy (p<0.001) and a lower dosage of RAAS antagonists (p<0.01) than younger patients. Younger patients were treated more intensively in hospitals with cardiac care (p<0.05). Patients aged >75 years were under-treated, independent of the hospital (n.s.). Multivariate analysis showed that age was the most influencing factor on survival (chi(2) 15.5, p<0.0001). Additional influencing factors of long-term survival were type of the ward (chi(2) 7.9, p<0.005) and pharmacologic treatment (chi(2) 6.2, p<0.02). CONCLUSION: Patients with chronic heart failure are still under-treated in clinical practice. Younger patients benefit from hospitals with specialized cardiac care. Elderly patients are obviously under-treated compared with younger patients. Of several clinical parameters, age was the only independent variable predicting long-term survival.

Adrenergic beta-Antagonists↗

PubMed2005

Incidence of normal values of natriuretic peptides in patients with chronic heart failure and impact on survival: a direct comparison of N-terminal atrial natriuretic peptide, N-terminal brain natriuretic peptide and brain natriuretic peptide.

AIMS: N-ANP, N-BNP and BNP are proven to be excellent markers for diagnosis and the prediction of outcome in heart failure patients. Published studies on this subject differ in respect of their design and are therefore difficult to compare. The EuroHeart Failure Survey was undertaken to evaluate the drug prescription rate; the cohort of this survey best reflects clinical practice. The purpose of the present study was to compare the three hormones in clinical practice for the purpose of diagnosis and the prediction of outcome. Attention was focused on patients with normal values and the implications of these on survival. METHODS AND RESULTS: Of 341 patients recruited in the Austrian centers of the survey, blood samples for the determination of N-ANP, N-BNP and BNP were taken from 112 patients. Mortality within the observation period was defined as the endpoint. Normal levels of the hormones were found in 5% of cases for N-ANP, 25% for N-BNP and 30% for BNP. The mortality of patients with normal values was low (0%, 3% and 6%, respectively) and occurred late (after more than 23 months). Above-median levels of all three hormones resulted in a comparable mortality (51% survival for N-ANP, 50% for BNP and 49% for N-BNP). CONCLUSIONS: In a clinical setting, the risk stratification for outcome is similar for N-ANP, N-BNP and BNP. More importantly, all hormones are reliable parameters to diagnose CHF using normal values as a cut-point. However, N-ANP appears to be more sensitive than BNP or N-BNP.

Aged↗

PubMed2004

Effect of single doses of SLV306, an inhibitor of both neutral endopeptidase and endothelin-converting enzyme, on pulmonary pressures in congestive heart failure.

SLV306, a potent neutral endopeptidase (NEP) inhibitor with additional endothelin-converting enzyme (ECE)-inhibitory activity, in doses of 200, 400, and 800 mg reduced pulmonary and right atrial pressures, although there was not a clear dose response. Systemic blood pressure, heart rate, and cardiac output were unaffected. SLV306 increased plasma natriuretic peptides and big endothelin-1 levels in a dose-dependent manner, confirming NEP and ECE inhibition. The combined inhibition of NEP and ECE may be useful in heart failure by reducing right and left cardiac filling pressures.

Aged↗

PubMed2004

Natriuretic peptides predict symptom-free survival and postoperative outcome in severe aortic stenosis.

BACKGROUND: The prognostic value of natriuretic peptides in aortic stenosis (AS) remains unknown. METHODS AND RESULTS: B-type natriuretic peptide (BNP), N-terminal BNP (NtBNP), and N-terminal atrial natriuretic peptide (NtANP) were determined in 130 patients with severe AS (mean age, 70+/-12 years; mean gradient, 64+/-21 mm Hg; valve area, 0.64+/-0.15 cm2) who were followed up for 377+/-150 days. Natriuretic peptides increased with NYHA class and with decreasing ejection fraction (EF). Even asymptomatic patients frequently had elevated neurohormones. Asymptomatic patients who developed symptoms during follow-up had higher BNP and NtBNP levels at entry compared with those remaining asymptomatic (median for NtBNP, 131 pmol/L [interquartile range, 50 to 202 pmol/L] versus 31 pmol/L [range, 19 to 56 pmol/L]; P<0.001). Symptom-free survival at 3, 6, 9, and 12 months for patients with NtBNP <80 versus > or =80 pmol/L was 100%, 88+/-7%, 88+/-7%, and 69+/-13% compared with 92+/-8%, 58+/-14%, 35+/-15%, and 18+/-15%, respectively (P<0.001). Seventy-nine patients eventually underwent surgery because of symptoms. Considering preoperative neurohormone levels, age, NYHA class, aortic valve area, EF, and presence of coronary artery disease, we found that neurohormones, EF, and NYHA class predicted survival; neurohormones predicted postoperative symptomatic status; and neurohormones and preoperative EF predicted postoperative EF. However, by multivariate analysis, NtBNP was the only independent predictor of outcome. CONCLUSIONS: In severe AS, natriuretic peptides provide important prognostic information beyond clinical and echocardiographic evaluation. NtBNP independently predicts symptom-free survival, and preoperative NtBNP independently predicts postoperative outcome with regard to survival, symptomatic status, and left ventricular function. Thus, neurohormones may gain particular importance for timing of surgery in asymptomatic severe AS.

Aged↗

PubMed2004

Beneficial effects of chronic low-frequency stimulation of thigh muscles in patients with advanced chronic heart failure.

AIMS: Patients with chronic heart failure (CHF) exhibit detrimental changes in skeletal muscle that contribute to their impaired physical performance. This study investigates the possibility of counteracting these changes by chronic low-frequency electrical stimulation (CLFS) of left and right thigh muscles. METHODS AND RESULTS: (mean+/-SD) 32 CHF patients (53+/-10 years) with an LVEF of 22+/-5%, NYHA II-IV, undergoing optimized drug therapy, were randomized in a CLFS group (CLFSG) or a control group (controls). The groups differed in terms of the intensity of stimulation, which elicited strong muscle contractions only in the CLFSG, whereas the controls received current input up to the sensory threshold without muscle contractions. Functional capacity was assessed by peak VO(2), work capacity, and a 6-min-walk (6-MW). Muscle biopsies were analyzed for myosin heavy chain (MHC) isoforms, citrate synthase (CS) and glyceraldehydephosphate dehydrogenase (GAPDH) activities. Peak VO(2)(mlmin(-1)kg -1) increased from 9.6+/-3.5 to 11.6+/-2.8 (P<0.001) in the CLFSG, and decreased from 10.6+/-2.8 to 9.4+/-3.2 (P<0.05) in the controls. The increase in the CLFSG was paralleled by increases in maximal workload (P<0.05) and oxygen uptake at the anaerobic threshold (P<0.01). The corresponding values of the controls were unchanged, as also the 6-MW values, the MHC isoform distribution, and both CS and GAPDH activities. In the CLFSG, the 6-MW values increased (P<0.001), CS activity was elevated (P<0.05), GAPDH activity decreased (P<0.01), and the MHC isoforms were shifted in the slow direction with increases in MHCI at the expense of MHCIId/x (P<0.01). CONCLUSIONS: Our results suggest that CLFS is a suitable treatment to counteract detrimental changes in skeletal muscle and to increase exercise capacity in patients with severe CHF.

Electric Stimulation Therapy↗

PubMed2004

Muscle strength as a predictor of long-term survival in severe congestive heart failure.

AIMS: The objective of the study was to test the relationship between isolated muscle strength and outcome, and its significance in the context of other exercise variables. METHODS AND RESULTS: 122 consecutive patients (LVEF 21+/-7%) were enrolled in the study. Isokinetic strength testing of the knee extensor and flexor muscles were performed. A subset of 51 patients underwent additional upright bicycle testing with gas exchange analysis. The outcome up to 60 months was defined by event-free survival (group A, n=59) or death (group B, n=34). Patients who had been transplanted were excluded from further analysis. The peak strength of the quadriceps muscle was comparable in both groups (N.S.). In contrast, the index (value adjusted for weight) did reveal significant differences (P<0.04), similar to the peak torque of the knee flexor muscle (P<0.04), whose index was even more significant with regard to differences (P<0.01). Multivariate analysis including muscle strength variables, pVO2 and workload into one model show that the flexor strength index is the only independent variable (x2=9 P<0.003). A cut-off point of 68 Nm x 100/kg in the strength index of the flexor muscles was used to establish a significant difference between groups with regard to outcome (P<0.01). Thus, the isokinetic strength of the knee flexor muscles is related to outcome. Moreover, this parameter is superior to variables such as peakVO2 and workload.

Aged↗

PubMed2004

The hemodynamic and neurohormonal effects of low doses of tezosentan (an endothelin A/B receptor antagonist) in patients with acute heart failure.

BACKGROUND: In previous studies (the RITZ project), tezosentan, an intravenous (i.v.)-balanced dual endothelin (ET-A/B) antagonist, in doses of 50 and 100 mg/h, improved the hemodynamics but not the clinical outcome of patients with acute heart failure (AHF). OBJECTIVE: To evaluate the effect of lower doses of tezosentan in patients with AHF. SUBJECTS AND METHODS: Included were 130 patients hospitalized due to AHF with dyspnea at rest, despite initial treatment, and were in need of hemodynamic monitoring with cardiac index (CI)<2.5 l/min/m(2) and wedge pressure > or = 20 mm Hg. Patients were randomized in a double-blind fashion to receive placebo or tezosentan: 0.2, 1, 5, or 25 mg/h for 24 h. RESULTS: The primary endpoint of the study, CI increase at 6 h of treatment, was significant in the 5 and 25 mg/h groups. Tezosentan induced a dose-dependent increase in CI and a decrease in wedge pressure, peaking after 3 h in the 5 and 25 mg/h groups. In the 1 mg/h group, this effect was smaller during the first 6 h and increased gradually, becoming significant at 24 h and beyond treatment discontinuation. There was no hemodynamic effect in the 0.2 mg/h arm. Type-B natriuretic peptide (BNP) decreased in the 1, 5, and 25 mg/h groups but not on placebo. Endothelin levels were significantly increased by the 5 and 25 mg/h groups but not in the lower (< or = 1 mg/h) tezosentan doses. Urine output decreased on the 25 mg/h dose. There was a trend towards improvement in patients' subjective dyspnea score and worsening heart failure events, mainly in the 1 mg/h group. CONCLUSIONS: In patients admitted with AHF, tezosentan doses of 1-25 mg/h are efficacious in improving the hemodynamics and reducing BNP. Tezosentan doses beyond 1 mg/h increased plasma endothelin levels and reduced urine output, probably limiting their clinical efficacy, as compared to tezosentan 1 mg/h.

Aged↗

PubMed2004

Interleukin-6 and B-type natriuretic peptide are independent predictors for worsening of heart failure in patients with progressive congestive heart failure.

BACKGROUND: Neurohormones and cytokines have been associated with poor prognosis in patients with congestive heart failure. However, direct comparisons between them are rare and the best predictor for worsening of heart failure remains to be elucidated. The aim of the study was to identify independent predictors for worsening of heart failure. METHODS: We studied 100 patients with congestive heart failure (LVEF <or=25%). Serum levels of interleukin-6 (IL-6), tumor necrosis factor (TNF)-alpha, aminoterminal atrial natriuretic peptide (N-ANP), B-type natriuretic peptide (BNP), aminoterminal B-type natriuretic peptide (N-BNP), norepinephrine (NE) and big endothelin (big ET) were measured at entry into the study. Univariate and stepwise multivariate regression analyses were performed to compare variables and clinical parameters. The end-point was defined as worsening of heart failure. RESULTS: During follow-up (mean 378 days), 30 patients reached the defined end-point. Univariate risk factors of worsening of heart failure were IL-6 (p = 0.0001), log BNP (p = 0.0001), log N-ANP (p = 0.0259), big ET (p = 0.0032), log N-BNP (p = 0.0495), NE (p = 0.0013) and LVEF (p = 0.0498). Multivariate regression analysis identified IL-6 as the strongest independent predictive value for worsening of heart failure (p = 0.0001), followed by log BNP (p = 0.0002). Mean IL-6 levels were 1.76 +/- 1.73 in stable patients and 4.62 +/- 7.98 pg/ml in patients who developed worsening of heart failure. Using a cut-off value of 1.66 pg/ml for IL-6 Kaplan-Meier freedom from worsening, heart failure was significantly higher in patients below this cut-off point compared with those above (p = 0.0002). CONCLUSIONS: IL-6 and BNP independently predict worsening of heart failure. A single measurement could help to identify patients at high risk for worsening of heart failure and these individuals should be monitored more closely.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed2004

Prostaglandin E1 induces vascular endothelial growth factor-1 in human adult cardiac myocytes but not in human adult cardiac fibroblasts via a cAMP-dependent mechanism.

Prostaglandin E(1) (PGE(1)) has been used to treat pulmonary hypertension and peripheral artery occlusive disease and has been successfully employed for pharmacological bridging to transplantation in patients with chronic end-stage heart failure. In addition to its vasoactive effects PGE(1) was shown to stimulate angiogenesis in animal models. Recently we showed that PGE(1)-induced angiogenesis in hearts of patients with ischemic heart disease. We proposed that the angiogenic action of PGE(1) is mediated by vascular endothelial growth factor (VEGF). In the present paper we studied a possible effect of PGE(1) on the expression of VEGF-1 in cultured human adult cardiac myocytes (HACM) and cultured human adult cardiac fibroblasts (HACFB), respectively, to identify a cellular source of VEGF-1 in patients treated with PGE(1). We also aimed to delineate mechanisms involved in a possible regulation of VEGF-1 by PGE(1) in these cells. When HACM, isolated from human myocardial tissue, were treated with PGE(1), a significant up to 3-fold increase in VEGF-1 production could be observed. These results could be confirmed on the level of specific mRNA expression as determined by real-time polymerase chain reaction. The effect of PGE(1) on VEGF-1 expression could be blocked by H089, an inhibitor of cAMP-dependent protein kinase A. In HACFB, also isolated from human myocardial tissue, no effect of PGE(1) on VEGF-1 production was seen. If this effect of PGE(1) is also operative in the in vivo situation, one could speculate that cardiac myocytes could be a cellular source of PGE(1)-induced VEGF-1 expression in patients treated with this drug.

Alprostadil↗

PubMed2004

Neurohumoral and hemodynamic effects of the selective endothelin antagonist darusentan in advanced chronic heart failure.

BACKGROUND: Endothelin antagonists represent a new approach to neurohumoral treatment in patients with chronic heart failure. In this study, the new selective endothelin-A receptor antagonist, darusentan, was compared with placebo for 3 weeks in patients with severe heart failure on top of standard treatment that included angiotensin-converting enzyme (ACE) inhibitors and beta-blockers. Effects on neurohormones and hemodynamics were evaluated. METHODS: Consecutive patients with severe heart failure (New York Heart Association [NYHA] Grade III) were included in this neurohumoral sub-study of an international, multi-center, double-blind, placebo-controlled study of darusentan, and randomized to darusentan (n = 23) or placebo (n = 8). The mean left ventricular ejection fraction was 19 +/- 6% at the beginning of the study. Patients were randomized to different dosage levels of darusentan (30, 100, or 300 mg) for 3 weeks. Hemodynamics were obtained by right heart Swan-Ganz catheterization at entry and end of study. Serial assessment of plasma brain natriuretic peptide (BNP), big-endothelin, and pro-atrial natriuretic peptide (pro-ANP) was performed. In the active treatment group, 1 patient died due to worsening heart failure, 1 patient received elective heart transplantation, and 2 patients stopped taking the medication due to vertigo. In the placebo group, 1 patient was excluded due to non-compliance. RESULTS: Overall, the mean dose of darusentan was 144 +/- 125 mg/day (30 mg: n = 8; 100 mg: n = 4; 300 mg: n = 7). Significant benefits in hemodynamic variables were found after 3 weeks only in patients receiving darusentan (baseline vs end of study: cardiac index: 2.0 +/- 0.3 vs 2.6 +/- 0.5 liters/min m(2), p < 0.0001; mean pulmonary artery pressure: 35 +/- 9 vs 33 +/- 8 mm Hg, p < 0.05; heart rate: 79 +/- 16 vs 71 +/- 10 beats/min, p < 0.01). A significant reduction in mean arterial blood pressure was observed with the endothelin antagonist (baseline 80 +/- 8 vs end 73 +/- 8 mm Hg, p < 0.01). BNP decreased significantly in patients with darusentan (90 +/- 87 at entry vs 63 +/- 67 fmol/ml after 3 weeks, p < 0.01), whereas big-endothelin remained unchanged. Pro-ANP tended to decrease in the active treatment group, but did not reach statistical significance. CONCLUSION: Significant hemodynamic and neurohumoral benefits were observed in patients with severe heart failure receiving the selective endothelin antagonist darusentan.

Atrial Natriuretic Factor↗