Bernhard Frey

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.

Significance of Morphological Abnormalities Detected by MRI in Patients Undergoing Successful Ablation of Right Ventricular Outflow Tract Tachycardia

BACKGROUND MRI can demonstrate subtle morphological changes of the right ventricle in patients with idiopathic right ventricular outflow tract tachycardia (RVOT). The present study examines the incidence and significance of right ventricular (RV) abnormalities detected by MRI with respect to the site of successful radiofrequency catheter ablation of the clinical tachycardia. METHODS AND RESULTS The study population comprised 20 patients (mean age, 40+/-12 years) undergoing elimination of recurrent RVOT by radiofrequency catheter ablation. MRI studies were performed before ablation to assess RV volumes and function, as well as structural abnormalities of the RV myocardium. Ten healthy age- and sex-matched subjects served as control subjects. The successful ablation sites, as documented by radiographs of the catheter position, were compared with MRI findings. Patients with RVOT showed no difference in respect to RV volumes and ejection fractions compared with control subjects. Whereas RV abnormalities were limited to prominent fatty deposits of the right atrioventricular groove extending into the inlet portion of the RV wall in 2 of 10 control subjects, MRI studies demonstrated morphological changes of the RV free wall in 13 (65%) of 20 patients with RVOT, including presence of fatty tissue (n=5), wall thinning (n=9), and dyskinetic wall segments (n=4). Eight of these patients had additional fat deposits, thinning, or a saccular aneurysm in the RV outflow tract, corresponding with the ablation site in 6 patients. CONCLUSIONS In RVOT, structural abnormalities of the right ventricle can be detected in a substantial number of patients despite normal RV volumes and global function. MRI abnormalities within the RV outflow tract are significantly associated with the origin of tachycardia.

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.

Prognostic value of heart rate variability in patients awaiting cardiac transplantation.

Time and frequency domain parameters of heart rate variability (HRV) were determined in patients with severe end stage heart failure awaiting cardiac transplantation (HTX). These parameters were then correlated with mortality to investigate the performance of HRV in discriminating between groups with high and low risk of death. The standard deviation of five consecutive RR intervals (SDANN) was found to be the parameter with the greatest sensitivity (90%) and specificity (91%). Patients with SDANN values of < 55 msec had a twenty‐fold increased risk of death (90% confidence limits: 4–118, P < 0.001). The results furthermore suggest that measurements of HRV are superior to other prognostic markers such as left ventricular ejection fraction, pulmonary artery wedge pressure, cardiac index, and serum sodium levels. We conclude that HRV is a powerful, noninvasive tool to assess the risk of death in candidates for HTX. HRV measurements can therefore be used as a supplement to other markers of risk to determine the optimal therapeutic strategy in patients with severe congestive heart failure.

Diurnal variation of ventricular response to atrial fibrillation in patients with advanced heart failure

Variability of ventricular rate was quantified by two measures of heart rate variability: the SD of the mean R-R interval (SDNN) and the SD of the 5-minute mean R-R interval (SDANN). In 35 patients with atrial fibrillation and advanced heart failure (left ventricular ejection fraction 20% +/- 9%, cardiac index 2.4 +/- 0.7 L/min/m2), SDNN and SDANN were compared to 13 preselected clinical and hemodynamic variables for prediction of outcome. During a 12-month follow-up period, 8 (23%) patients deteriorated clinically; 3 (9%) died, and 5 (14%) underwent heart transplantation. SDNN and SDANN correlated to the difference of the mean R-R interval between night (2 AM to 3 PM) and day (11 AM to noon) with r values of 0.62 and 0.77, respectively. From 15 preselected variables, only SDANN (chi 2 = 6.7, p = 0.01) was independently associated with survival on multivariate analysis. Dichotomized SDANN at 100 msec accurately predicted 12-month survival in 28 (80%) patients (relative risk = 9.77, p = 0.001). In conclusion, analysis of heart rate variability is useful in quantifying diurnal variation of ventricular rate in atrial fibrillation and might be useful in predicting survival in patients with advanced heart failure.

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.

Ablation of atrial tachycardia originating from the vicinity of the atrioventricular node: significance of mapping both sides of the interatrial septum.

OBJECTIVES The purpose of the study was to examine the value of right- and left-sided mapping to identify the site of tachycardia origin. BACKGROUND Focal atrial tachycardia may originate from the vicinity of the atrioventricular node from either side of the interatrial septum. METHODS In 16 patients undergoing radiofrequency catheter ablation of perinodal atrial tachycardia, activation mapping of the right and left side of the interatrial septum was performed. RESULTS Atrial tachycardia originated from the right side of the interatrial septum in 10 patients (group A) and from the left side in 6 patients (group B). On the right side, earliest atrial activity preceded the onset of the P-wave by 49 +/- 15 ms in group A and by 38 +/- 8 ms in group B (NS), and it preceded the signal recorded from the right atrial appendage by 59 +/- 19 ms in group A and by 60 +/- 13 ms in group B (NS). On the left side, earliest activity preceded the onset of the P-wave by 27 +/- 16 ms in group A and by 51 +/- 6 ms in group B (<0.01), and it preceded the signal obtained from the right atrial appendage by 38 +/- 19 ms in group A and by 73 +/- 9 ms in group B (<0.01). Atrial tachycardias were successfully eliminated in all patients without impairment of atrioventricular conduction. During follow-up, two patients had a recurrence of tachycardia. CONCLUSIONS Mapping of only the right side cannot exclude a left-sided origin. Therefore, mapping of both sides of the interatrial septum is required prior to ablation of focal atrial tachycardia originating from the vicinity of the atrioventricular node.

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.