Brigitte Stanek

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.

Value of cardiopulmonary exercise testing and big endothelin plasma levels to predict short-term prognosis of patients with chronic heart failure.

OBJECTIVES We tested the hypothesis that, in patients with stable heart failure, measuring big endothelin-1 (ET-1) plasma level at rest predicts short-term prognosis better than peak oxygen consumption (VO2max) at exercise. BACKGROUND Cardiopulmonary exercise testing and evaluation of neurohumoral plasma factors are established tools to estimate survival in patients with heart failure. No data, however, exist comparing the prognostic value of both marker categories simultaneously. METHODS Two hundred twenty-six heart failure patients were studied in regard to a combined end point of death and prioritization for urgent cardiac transplantation within 1 year follow-up. RESULTS During the study period 149 patients were without cardiac events (group A), 69 patients died or were urgently transplanted (group B) and 8 patients were alive after a nonurgent heart transplant operation. Norepinephrine (p < 0.0001), atrial natriuretic peptide (p < 0.001), big endothelin plasma levels (p < 0.0001 as well as workload, VO2max and achieved percentage of predicted peak oxygen consumption (pVO2max) (all p < 0.0001) differed significantly between groups A and B. In multivariate stepwise regression analysis, however, only big ET-1 plasma concentration (chi2=74.4, p < 0.0001), New York Heart Association function class (chi2=33.9, p < 0.0001), maximal workload (chi2=7.2, p < 0.01, and plasma atrial natriuretic peptide (ANP) concentration (chi2=4.6, p < 0.05) were independently related to outcome. Peak oxygen consumption or pVO2max did not reach statistical significance in this model. Event-free survival rates were significantly lower in patients with a big ET-1 level of 4.3 fmol/ml or more than with lower big ET-1 levels (p < 0.0001). CONCLUSION We conclude that in patients with chronic heart failure who are stable on oral therapy measuring big ET-1 and ANP plasma levels may be a valuable noninvasive adjunct to improve the prognostic accuracy of detecting high risk patients compared with exercise testing alone.

Effects of Endothelin A Receptor Blockade on Endothelial Function in Patients With Chronic Heart Failure

Background —Chronic heart failure (CHF) is associated with impaired endothelium-dependent vasodilation and increased basal vascular tone due, in part, to elevated endothelin-1 plasma levels. In the present study, we investigated whether a reduction of vascular tone using an endothelin A receptor blocker attenuates the impairment of endothelium-dependent, flow-mediated vasodilation (FMD). Methods and Results —Twenty-one patients with CHF randomly received either the endothelin A receptor blocker LU 135252 (30 mg/d, n=7; 300 mg/d, n=7) or a placebo (n=7). Using high-resolution ultrasound, FMD and endothelium-independent, nitroglycerin-induced dilation of the brachial artery were assessed at baseline in the 21 patients with CHF and in 11 controls and after 3 weeks treatment in the 21 patients with CHF. FMD at baseline was impaired in all 21 patients with CHF (3.2±2%) when compared with the 11 controls (9.7±4.9%;P =0.0005). In comparison with baseline, FMD significantly improved after 3 weeks of treatment with LU 135252 in all 14 patients receiving it (from 3.0±2.0% to 4.9±2.9%;P =0.04), but FMD remained unchanged with placebo. Subgroup analysis, according to different dosages, revealed a significant increase of FMD compared with baseline (from 2.4±1.5% to 5.5±2.4%;P =0.03) in the patients treated with the low-dose (30 mg/d), whereas a high dose of 300 mg/d failed to increase FMD significantly. Improvement in the high-dose group, however, may have been masked by reduced vasodilator capacity due to a significant increase in vessel size (from 4.8±0.4 to 5.1±0.7 mm;P =0.03). Conclusions —These results suggest that endothelin A receptor blockade improves FMD in CHF patients.

Moderate-intensity exercise training with elements of step aerobics in patients with severe chronic heart failure

OBJECTIVE To evaluate whether a specific program of moderate-intensity step aerobics training may be sufficient to improve the exercise tolerance of patients with severe chronic heart failure. PATIENTS Twenty-six patients (22 men, 4 women; mean +/- SD age, 54 +/- 9yrs) with a history of severe chronic heart failure (left ventricular ejection fraction of 18% +/- 8%). STUDY DESIGN Prospective, randomized, controlled trial. Patients were randomized into exercise and control groups. All patients underwent a clinical examination and a ramp pattern cycle exercise test before and after the observation period. The exercise group underwent a moderate-intensity (50% of peak oxygen uptake) 12-week training program, progressing to 100 minutes per week of step aerobics and 50 minutes per week of cycling. The control group did not perform a training program. MAIN OUTCOME MEASURES Peak oxygen uptake, peak workload, percent of predicted power ability. RESULTS Significant increases in peak oxygen uptake (15 +/- 3.4 to 18.5 +/- 2.9mL/kg/min; p = .001), peak workload (77 +/- 26 to 99 +/- 31 watts; p = .000), and percent of predicted power ability (43% +/- 10% to 56% +/- 13%; p = .000) were observed in the exercise group. No significant changes in baseline parameters occurred in the control group. There were no critical changes in heart rate or blood pressure in either group. CONCLUSION Moderate-intensity step aerobics training significantly increases peak oxygen uptake and peak workloads in patients with severe chronic heart failure.

Bridging to heart transplantation: prostaglandin E1 versus prostacyclin versus dobutamine

BACKGROUND Prostaglandin E1 (PGE1) and prostacyclin have potent pulmonary and systemic vasodilating properties. This prospective, randomized trial compared PGE1 vs prostacyclin vs. low-dose dobutamine in patients with low-output heart failure awaiting heart transplantation (HTx) who were refractory to oral treatment. METHODS Patients in advanced heart failure in New York Heart Association (NYHA) Class IV, with a cardiac index < or = 2.5 L/minute/m2 and a pulmonary capillary wedge pressure > or = 20 mmHg, who were listed for HTx were studied. In an inpatient study phase of 12 hours duration, therapy was aimed to increase cardiac output by 20% or more, when compared to baseline values, and to achieve a reduction of pulmonary vascular resistance below 550 dyn.s/cm-5m-2. During a long-term outpatient phase, the drugs were continuously infused to bridge these patients to HTx using three combined negative endpoints (worsening heart failure, serious adverse events, death) for analysis. RESULTS Sixty-eight patients were enrolled, 30 patients on PGE1, 8 patients on prostacyclin, and 30 patients on dobutamine. During the inpatient study phase, maximum doses were 22 +/- 1.8 ng/kg/minute for PGE1, 7 +/- 1 ng/kg/minute for prostacyclin and 5 +/- 0.4 micrograms/kg/minute for dobutamine. During the inpatient study phase 21 patients failed, 4/30 (13%) patients on PGE1, 4/8 patients on prostacyclin (50%), and 13/30 (43%) on dobutamine (p < 0.05). Long-term continuous intravenous drug infusion in outpatients was begun in 26 patients on PGE1, in 4 patients on prostacyclin, and in 17 patients on dobutamine. Infusion therapy lasted for 88 +/- 14 days in the PGE1 group with 31 +/- 22 days in the prostacyclin group, and 30 +/- 8 days in the dobutamine group (NS). During the outpatient phase 23 patients reached a negative endpoint with 16 patients developing worsening heart failure, 5 severe adverse events and 2 deaths. Seven out of 26 (27%) failed on PGE1, 4/4 (100%) failed on prostacyclin, and 12/17 (71%) failed on dobutamine (p < 0.05, log rank test). Because prostacyclin treatment was ineffective in the first 8 patients, this trial arm was stopped prematurely. CONCLUSIONS The findings from this prospective open pilot trial suggest that continuous PGE1 infusions at individualized dosages can be useful in certain patients as a pharmacologic bridging procedure with reduced risk to develop worsening heart failure before HTx compared to prostacyclin and dobutamine. Further comparative studies are warranted to investigate the effects of PGE1 among other bridging agents.

Effect of β1 blockade with atenolol on progression of heart failure in patients pretreated with high-dose enalapril

The survival benefit of β‐blocker treatment in patients with heart failure has been established in recent trials. Yet, the impact of β‐blockers added on high dose angiotensin converting enzyme inhibitors has not been reported.

Angiogenesis stimulation in explanted hearts from patients pre-treated with intravenous prostaglandin E1

BACKGROUND Prostaglandin E(1) (PGE(1)) is a potent vasodilator and induces angiogenesis in animal tissues. Previous clinical studies demonstrated that PGE(1) improves hemodynamic parameters in patients with heart failure listed for heart transplantation (HTX). Therefore, we designed a retrospective immunohistochemistry study to investigate various markers of angiogenesis using hearts explanted from PGE(1)-treated patients with idiopathic dilated cardiomyopathy (IDCM). METHODS AND RESULTS We investigated neovascularization in 18 hearts explanted from patients with IDCM: 9 patients received treatment with chronic infusions of PGE(1) for end-stage heart failure before HTX, whereas the remaining patients with IDCM did not receive PGE(1) and served as controls. We used immunoreactivity against CD34, von Willebrand factor (vWf), vascular endothelial growth factor (VEGF), and MIB-1 (Ki-67) to quantify angiogenesis, and used sirius red staining to determine the degree of fibrosis. Compared with the control group, PGE(1)-treated patients had significantly more CD34-, vWf- and MIB-1-positive cells in the sub-endocardium, myocardium and sub-epicardium (p < 0.01). The degree of fibrosis in the hearts of PGE(1)-treated patients was significantly lower than in control patients (p < 0.05), but we did not see any difference in the percentage of muscle mass. Finally, throughout the ventricles, we found significantly more VEGF-positive capillaries in the PGE(1) group (p < 0.0001). CONCLUSIONS The data suggest that PGE(1) could be a potent inducer of angiogenesis and the angiogenic factor VEGF, and could cause reduced fibrosis in the failing human heart.

Prognostic power of neurohumoral parameters in chronic heart failure depends on clinical stage and observation period

BACKGROUND Endothelin (ET) and natriuretic peptides have prognostic significance in chronic heart failure (CHF). Because stimuli for forming these neurohormones differ, this study investigates whether their prognostic power depends on clinical stage and on length of the observation period. METHODS Plasma big ET, B-type natriuretic peptide (BNP), N-terminal BNP (N-BNP), and N-terminal atrial natriuretic peptide (N-ANP), in addition to 11 clinical and hemodynamic variables, were obtained from 452 patients with left ventricular ejection fraction (LVEF) </=35%. According to their New York Heart Association class and LVEF, patients were stratified into Group A, mild CHF (n = 114); Group B, moderate CHF (n = 210); and Group C, severe CHF (n = 128). To predict the combined end-point of death or urgent heart transplantation, a multivariate analysis was performed after an observation period of up to 1, 2, and 3 years in all patients and in each sub-group. RESULTS Best independents predictors were as follows: All patients: up to 1 year, big ET (p < 0.0001, chi-square = 59); and 2 and 3 years, log N-ANP (p < 0.0001, chi-square = 68; p < 0.0001, chi-square = 89). Group A: up to 2 and 3 years, log N-ANP (p < 0.001, chi-square = 12; p < 0.0001, chi-square = 25). Group B: up to 1 and 3 years, log N-ANP (p < 0.0001, chi-square = 16; p < 0.0001, chi-square = 22); and 2 years, log N-BNP (p < 0.0001, chi-square = 19). Group C: up to 1, 2, and 3 years, big ET (p < 0.0001, chi-square = 23; p < 0.0001, chi-square = 22; p < 0.0001, chi-square = 20). CONCLUSION Big ET was the best independent marker for 1-year prognosis in severe CHF, whereas natriuretic peptides (especially N-ANP) were better markers for 2- and 3-year prognoses in mild and moderate CHF.

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.

Effect of Prostaglandin E1 Infusion in Severe Chronic Heart Failure

Prostaglandin E1 (PGE1, alprostadil) is a potent vasodilating agent that is frequently used to resolve cardiogenic pulmonary hypertension. To investigate the effect of PGE1 in refractory chronic heart failure in a double-blind trial, twenty patients (17 men, 3 women, 58 +/- 2 years, cardiac index < or = 2.5 l/min/m2, pulmonary capillary wedge pressure > or = 20 mmHg), who were in NYHA functional class IV on optimized treatment with ACE inhibitors and furosemide were infused with 30 ng/kg/min PGE1 or placebo through 48 hours. All patients received a concomitant therapy with standardized catecholamine infusions which were given 24 hours in advance and were continued throughout the study. There was no difference in baseline values between the randomized groups before PGE1 or placebo was added. PGE1 resulted in decrements in pulmonary artery pressure (from 37 +/- 4 to 30 +/- 4 mmHg; p < 0.01), pulmonary capillary wedge pressure (from 26 +/- 4 to 19 +/- 3 mmHg p < 0.001) systemic vascular resistance index (from 2048 +/- 213 to 1506 +/- 13 dyn.sec/cm5.m2, p < 0.05) and in increments in cardiac index and stroke volume index (from 2.2 +/- 0.1 to 2.8 +/- 0.2 l/min.m2; p < 0.05 and from 23 +/- 2 to 28 +/- 2 l/m2; p < 0.05, respectively). Moreover, creatinine clearance increased (p < 0.05). Placebo infusions did not result in any hemodynamic or renal effect. Between groups percentage hemodynamic changes differed with respect to pulmonary artery pressure (p < 0.01), cardiac index (p < 0.05), stroke volume index (p < 0.05) and pulmonary vascular resistance index (p < 0.05). It is concluded that intravenous infusions with PGE1 may add further substantial benefit to the hemodynamic state in refractory heart failure patients who are already stabilized on i.v. inotropic support with catecholamines.