Richard Pacher

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 ≥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.

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

OBJECTIVESnThe study assessed the relative predictive potency of neurohumoral factors in patients with advanced left ventricular (LV) dysfunction during neurohumoral blocking therapy.nnnBACKGROUNDnThe 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.nnnMETHODSnPlasma 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.nnnRESULTSnThirty-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.nnnCONCLUSIONSnIn 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.

First Clinical Experience With the DeBakey VAD Continuous-Axial-Flow Pump for Bridge to Transplantation

BACKGROUNDnA shortage of donor organs and increased numbers of deaths of patients on the waiting list for cardiac transplantation make mechanical circulatory support for a bridge to transplantation a standard clinical procedure. Continuous-flow rotary blood pumps offer exciting new perspectives.nnnMETHODS AND RESULTSnTwo male patients (ages 44 and 65 years) suffering from end-stage left heart failure were implanted with a DeBakey VAD axial-flow pump for use as a bridge to transplant. In the initial postoperative period, the mean pump flow was 3.9+/-0.5 L/min, which equals a mean cardiac index (CI) of 2.3+/-0.2 L. min(-1). m(-2). In both patients, the early postoperative phase was characterized by a completely nonpulsatile flow profile. However, with the recovery of heart function 8 to 12 days after implantation, increasing pulse pressures became evident, and net flow rose to 4.5+/-0.6 L/min, causing an increase of mean CI up to 2.7+/-0.2 L. min(-1). m(-2). Patients were mobilized and put through regular physical training. Hemolysis stayed in the physiological range and increased only slightly from 2. 1+/-0.8 mg/dL before surgery to 3.3+/-1.8 mg/dL 6 weeks after implantation.nnnCONCLUSIONSnThe first clinical implants of the DeBakey VAD axial-flow pump have demonstrated the device to be a promising measure of bridge-to-transplant mechanical support.

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

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.

Evaluation of esophageal tracheal combitube in cardiopulmonary resuscitation.

Prompt establishment of an airway is a primary goal in CPR of nonbreathing and unconscious patients. The esophageal tracheal combitube (ETC) is a new airway, designed for emergency intubation providing sufficient ventilation whether the airway is placed into the trachea or into the esophagus. We evaluated the effectiveness of the ETC in 31 patients during CPR. Blood gas analyses obtained during esophageal placement of the ETC showed results comparable to those of ventilation with a conventional endotracheal airway (ETA). The ETC appeared to oxygenate and ventilate patients adequately without complications. The efficacy, safety, and ease of insertion ensure rapid airway control. It is concluded that the ETC provides a sufficient alternative to the ETA whenever ideal conditions or trained staff for endotracheal intubation are not immediately available.

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

OBJECTIVESnWe 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.nnnBACKGROUNDnCardiopulmonary 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.nnnMETHODSnTwo 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.nnnRESULTSnDuring 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).nnnCONCLUSIONnWe 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.

Relationship between neopterin and granulocyte elastase plasma levels and the severity of multiple organ failure

In a series of 56 patients (24 uncomplicated postoperative and 32 septic patients), neopterin and elastase alpha 1 protease inhibitor complex (E-alpha 1 PI) plasma levels were measured daily. The clinical course of each patient was evaluated with the Multiple Organ Failure (MOF) score according to Goris. Neopterin could differentiate between septic and nonseptic patients (p less than .001), and E-alpha 1 PI between septic nonsurvivors and nonseptic patients only (p less than .01). In septic patients, acute pulmonary insufficiency was indicated by elevated E-alpha 1 PI values (greater than or equal to 400 micrograms/L) 1 day before mechanical ventilation was performed with a sensitivity of 81% and a specificity of 82%. Defining a patient with MOF whose score was greater than or equal to 5 as a high-risk septic patient, a comparison neopterin greater than or equal to 40 nmol/L and E-alpha 1 PI greater than or equal to 400 micrograms/L, measured 1 day before the evaluation of an MOF score of greater than or equal to 5 yielded a sensitivity of 91% and a specificity of 99% when patients fulfilled both criteria. We conclude that neopterin and E-alpha 1 PI might be useful parameters for the diagnosis of septicemia and monitoring of the clinical course in septic patients. Moreover, they might indicate the possible central role of macrophage and PMN activation in the development of MOF.

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.

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

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).

Clinical and experimental evidence of prostaglandin E1-induced angiogenesis in the myocardium of patients with ischemic heart disease

OBJECTIVEnProstaglandin E1 (PGE-1) is a potent vasodilative agent which has been used to bridge patients with chronic heart failure listed for heart transplantation (HTX). In various experimental settings PGE-1 appears to stimulate angiogenesis by inducing vascular endothelial growth factor expression. This observational clinical study sought to investigate the angiogenic effects of PGE-1 in the failing human heart.nnnMETHODSnNeovascularization was investigated in 14 explanted hearts from patients with ischemic cardiomyopathy (ICMP) who had been bridged to HTX with PGE-1 (8+/-1 mg/kg/min, 97+/-75.6 days) and compared with 14 hearts who did not receive PGE-1 prior to HTX. In three sectional areas obtained from the left ventricular wall CD34, von Willebrand factor (vWf), nuclear Ki67 (MIB-1), and VEGF were quantified by immunohistochemistry to estimate capillary density and endothelial cell proliferation. Additionally, to investigate a possible angiogenic effect of PGE-1 in vitro, cultured human coronary artery smooth muscle cells (HCASMCs) were treated with PGE-1.nnnRESULTSnPGE-1-treated patients had significantly more CD34- and vWf-positive cells in the subepicardium (both P<0.01), myocardium (both P<0.0001) and subendocardium (P<0.01 and P<0.001) as compared to the nonPGE-1 group. Proliferative endothelial activity expressed by the presence of MIB-1- and VEGF-positive cells (both P<0.0001 in all layers) was increased more than twofold. Addition of PGE-1 to HCASMCs in cell culture resulted in a significant increase in VEGF production (164.0+/-19.7 pg/10(5) cells/24 h, P<0.005) as compared to the control cell line (66.6+/-8.7 pg/10(5) cells/24 h, P<0.005).nnnCONCLUSIONSnOur data demonstrate that PGE-1 is a potent stimulator of angiogenesis via upregulation of VEGF expression. The induction of therapeutic angiogenesis in patients with severe ICMP might explain the favorable clinical outcome in PGE-1 treated patients until HTX.