HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Malcolm Underwood Gebrine El Khoury Martin Goenen Robert Dion Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Noirhomme, P. Articles by Dion, R. Search for Related Content PubMed PubMed Citation Articles by Noirhomme, P. Articles by Dion, R.

Eur J Cardiothorac Surg 1999;16:63-67
© 1999 Elsevier Science NL

The effect of chronic mechanical circulatory support on neuroendocrine activation in patients with end-stage heart failure

^a Department of Cardiovascular and Thoracic Surgery, Cliniques Universitaires Saint-Luc, Brussels, Belgium
^b Department of Intensive Care, Cliniques Universitaires Saint-Luc, Brussels, Belgium

Corresponding author. Tel.: +32-2-7646107; fax: +32-2-7646208

	Abstract

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion References

 
Objective: To evaluate if the improvement of patients supported with a Novacor was associated with a normalization in neuroendocrine activity. Methods: Six patients had a Novacor implanted for end-stage heart failure. Four patients were transplanted after a mean of 4.5 months (range 3–6). One patient was weaned after 5 months and one died of a cerebral haemorrhage 5 weeks after implantation. Analysis of neuroendocrine activity was made prior to implantation and after 14, 30, 60 and 90 days. Levels of aldosterone, renin, cortisol, testosterone and T3 were measured using radio-immunoassays. Twenty-four hour urinary collections were made for assessment of adrenaline and noradrenaline excretion. Results: Renin activity fell to normal after 14 days (16±3.0 ng/ml per h to 4.28±2.1 ng/ml per h, P<0.05) and was maintained at 90 days. A similar picture was seen with aldosterone (1.5±0.4 nM to 0.12±0.07 nM, P<0.05). Norepinephrine (67.46±14.1 µg/24 h) and epinephrine 12.9±2.5 µg/24 h) fell to normal physiological levels during the same time period. Cortisol levels were above normal pre-implantation but fell by day 30 (665.25±80.0 nM to 461.8±43.0 nM, P<0.01). T3 and testosterone were lower than normal pre-implantation (T3 50±9.5 ng/dl vs. 90–200 ng/dl, testosterone 6.83±1.7 nM vs. 13–35 nM). T3 normalized after 90 days (81±11.7 ng/dl) and testosterone after 60 days (16.3±1.7 nM). Conclusion: Neuroendocrine function is abnormal in patients with cardiac failure who require circulatory support. The Novacor improved this, but metabolic recovery was delayed. The positive effect on the neuroendocrine axis, in the absence of activation of other endocrine systems, suggests that prolonged support may be well tolerated.

Key Words: Neuroendocrine system • Heart failure • Left ventricle assist device

	1. Introduction

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion References

 
Activation of neuroendocrine systems is well recognized in patients with congestive cardiac failure [1,2], and several of the pharmocological treatments have been shown to favourably reduce the level of this activity [3,4]. Marked clinical improvements have been noted in this group of patients when they are treated with mechanical assist devices [5], but little work has addressed the issue of neuroendocrine activation in patients with congestive heart failure who have implantable left-ventricular assist devices (LVAD) used [6]. The aim of this study was to evaluate if the clinical improvement in patients awaiting cardiac transplantation, and supported with an LVAD, was associated with a normalization of neuroendocrine activity, and if this was the case, how long support needed to be implemented before a beneficial effect was observed.

	2. Materials and methods

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion References

 
2.1. Patient population
We studied six patients who had implantation of a Novacor for end-stage heart failure between July 1994 and July 1997. The mean age of the patients was 38 years (range 19–50), the mean weight was 72 kg (range 48–105). Two patients had implantation for ischaemic heart disease, two patients for dilated cardiomyopathy, one patient for late graft failure following cardiac transplantation and the final patient for toxic cardiomyopathy. All patients showed the haemodynamic manifestations of cardiac failure pre-implantation, the mean cardiac index was 1.8 l/m² (range 1.4–2.3) with a mean pulmonary capillary-wedge pressure of 28 mmHg (range 23–33). Prior to LVAD implantation, all patients received inotropic support in the form of dobutamine (5–10 µg/kg per min) and/or dopamine (2–10 µg/kg per min) and the latter two patients were treated with milrinone.

2.2. LVAD implantation
The Novacor N-100 left ventricular assist device (LVAD) (Novacor Medical Division, Baxter Healthcare Corporation, Oakland, CA) was implanted in each patient via a median sternotomy after the instigation of cardiopulmonary bypass. Briefly, the device was placed in a rectus sheath pouch. The outflow conduit was anastomosed to the ascending aorta and the inflow conduit was inserted into the left ventricular cavity after excision of a core of apex tissue under cardioplegic arrest. Implantation was performed according to previously published protocols [7].

2.3. Post-operative care
All patients were anticoagulated the day following LVAD implantation using coumadin (INR2.5–3), aspirin (100 mg/day) and dipyridamole (300 mg/day). Patients were weaned from the device if during a maximal stress test the cardiac index was >5.5 l/min per m² and the left ventricular end-diastolic diameter was <55 mm as assessed using echocardiography during an off-pump trial. Two patients developed superficial pocket infections and one patient had a blood transfusion. No patient required additional medication following weaning of inotropes after device implantation.

2.4. Assessment of neuroendocrine activation
To assess neuroendocrine activation in these patients, serum levels of aldosterone, renin, cortisol, testosterone and thyroxine were measured as well as the urinary excretion of catecholamines (adrenaline, noradrenaline). Samples were collected immediately prior to LVAD implantation and after 14, 30, 60 and 90 days of support.

2.4.1. Sample collection
Venous blood was collected from a 18 or 20 gauge intravenous cannula. In all patients, samples were taken after 20–30 min rest in the supine position at 08:00 h. Samples were taken into tubes containing EDTA (1–6 mg/ml blood), chilled on ice and transported directly to the laboratory. Samples were then centrifuged within 2 h (2500 rev./min, 4°C for 15 min) and plasma transferred to polypropylene tubes and stored at -70°C for subsequent batch analysis. Twenty-four hour urinary collections were made for the analysis of adrenaline and noradrenaline excretion.

2.4.2. Neuroendocrine assays
Plasma renin activity (PRA) was measured by radio-immunoassay (RIA) of generated angiotensin I (Medix Angiotensin Test, Medix Biochemica, Finland). Aldosterone and testosterone levels were also measured using RIA techniques (Abbot Diagnostics Division, Belgium). T3 levels were measured using Riabead RIA kits (Abbot Diagnostics Division, Belgium). Cortisol levels were measured using a (¹²⁵I) Cortisol solid phase radioimmunoassay (Becton Dickinson Benelux SA, Belgium). Adrenaline and noradrenaline excretion in urinary samples was made using high performance liquid chromatography (HPLC), and levels recorded after generation of standard curves.

2.5. Statistical analysis of results
Results are presented as mean±SEM for all variables. Changes over time were assessed using the analysis of variance. Statistical differences between time points were made using the modified Bonferroni test. A P value of <0.05 was taken as statistically significant.

	3. Results

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion References

 
3.1. Clinical outcome
Four patients were successfully transplanted after LVAD support for a mean of 4.5 months (range 3–6). One patient was weaned from the device after 5 months of support and the final patient died of a cerebral haemorrhage 5 weeks after implantation. All patients were weaned of inotropes after 1 week of LVAD support and at this time period all showed significant haemodynamic improvements. The mean cardiac index increased from 1.8 l/m² to a mean of 3.1 l/m².

3.2. Neuroendocrine levels
Plasma renin activity fell significantly to below normal levels (<5 mg/ml per h) after 14 days of support (16±3.0ng/ml to 4.28±2.1ng/ml, P<0.05) and normal values were maintained at the 90 day sampling period (Fig. 1). A similar picture was seen with aldosterone levels (1.5±0.4 nM to 0.12±0.07 nM, P<0.05). Urinary norepinephrine excretion fell to below normal levels (120±30 µg/24 h) during the same time frame (to 67.46±14.1 µg/24 h), and a similar picture was seen for noradrenaline excretion (normal 100±25 µg/24 h to 12.9±2.5 µg/24 h. Plasma cortisol levels were also above normal values (400±140 nM) pre-LVAD implantation, but fell to within normal levels at the 30 day sampling period (665.25±80.0 nM to 461.8±43 nM, P<0.01); these were maintained at the 90 day sampling period (Fig. 2).

View larger version (9K): [in this window] [in a new window]   Fig. 1. Variation in renin levels following Novacor implantation. NL, normal levels.

View larger version (13K): [in this window] [in a new window]   Fig. 2. Variation in cortisol levels following Novacor implantation. NL, normal levels.

View larger version (13K): [in this window] [in a new window]   Fig. 3. Variation in T3 levels following Novacor implantation. NL, normal levels.

View larger version (11K): [in this window] [in a new window]   Fig. 4. Variation in testosterone levels following Novacor implantation. NL, normal levels.

	4. Discussion

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion References

Plasma renin activity and aldosterone levels were high in our patient group prior to LVAD implantation. Both reached normal levels after 2 weeks of support and this normalization of activity was maintained for the duration of LVAD assistance. Observationally, we noted physiological variations in aldosterone levels during hypovolaemic episodes whilst on the LVAD, which adds confirmation to the fact that the renin-angiotensin axis was now normal in these patients. We measured urinary catecholamines in preference to plasma levels because we felt these measurements better reflected daily secretion rather than isolated peaks of activity. Pre-implantation, plasma estimates of catecholamine may also be affected by inotropic support and therefore not be representative of only neuroendocrine activation. All patients had abnormally high excretion of both adrenaline and noradrenaline, both of which rapidly normalized after LVAD support, in association with the improvement of systemic haemodynamics.

Cortisol levels may increase following a variety of stress-inducing events, and high levels can be found in patients without left ventricular dysfunction who are being treated for a variety of illnesses on intensive-care [2]. The maintenance of normal levels in our patient group after introduction of the Novacor device suggest that implantation of the device itself does not induce a significant stress response, or if it does, this is outweighed by the improvements in cardiac output and perfusion pressure. A reduction in T3 and testosterone levels which may accompany LV failure do not represent primary glandular dysfunction but reflect the metabolic effects of chronic illness. Both these indices were reduced prior to support in our patients but recovery was delayed for a period of nearly 3 months. The observation of this latent period prior to metabolic recovery, suggests that perhaps these are important indices to consider, along with measurement of cardiac recovery, before weaning the device in selected patients with reversible cardiomyopathy. It may be sensible in these patients to wait for metabolic as well as cardiac recovery, so the patient is in an optimal condition prior to explantation, although we accept that this recommendation requires further validation in larger cohorts of patients.

Although this study represents a small series of patients, we have confirmed the finding of others that neuroendocrine function is abnormal in patients with cardiac failure who require mechanical circulatory support. The implantation of the Novacor device results in a significant improvement in these parameters, but metabolic recovery is delayed. This positive effect of the Novacor on the neuroendocrine axis, in the absence of activation of other endocrine systems suggests that prolonged support may be well tolerated if thromboembolic and infectious complications could be avoided.

	References

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion References

 

1. Francis G.S., Rector T.S., Cohn J.N. Sequential neurohumoral measurements in patients with congestive cardiac failure. Am Heart J 1988;116:1464-1468.[Medline]
2. Francis G.S., Goldsmith S.R., Levine T.B., Olivera M.T., Cohn J.N. The neurohumoral axis in congestive heart failure. Ann Intern Med 1984;101:370-377.
3. Covil A.B., Shaer G.L., Sealey J.E., Laragh J.H., Cody R.J. Suppression of the renin-angiotensin system by intravenous digoxin in chronic congestive heart failure. Am J Med 1983;75:445-447.[Medline]
4. Gheorghiado M., Hall V., Lakier J.R., Goldstein S. Comparative haemodynamic and neurohumoral effects of intravenous captopril and digoxin and their combination in patients with severe heart failure. J Am Coll Cardiol 1989;13:134-142.[Abstract]
5. Jaski R.E., Branch K.R., Adamson R., Peterson K.L., Gordon J.B., Hoagaland P.M., Smith S.C., Daily P.O., Dembritsky D.B. Exercise haemodynamics during long-term implantation of a left ventricular assist device in patients awaiting heart transplantation. Am Coll Cardiol 1993;22:1574-1580.[Abstract]
6. James K.B., McCarthy P.M., Thomas J.D., Vargo R., Hobbs R.E., Sapp S., Bravo E. Effect of the implantable left ventricular assist device on neuroendocrine activity in heart failure. Circulation 1995;92(Suppl. II):191-195.[Abstract/Free Full Text]
7. Pennington D.G., Lawrence R. Implantation technique for the Novacor left ventricular assist system. J Thorac Cardiovasc Surg 1994;108:604-608.[Abstract/Free Full Text]
8. Frazier O.H., Rose E.A., Macmanus O., Burton N.A., Lefrac E.A., Poirier V.L., Dasse K.A. Multicentre clinical evaluation of the Heartmate 1000 JP left ventricular assist device. Ann Thorac Surg 1992;53:1080-1090.[Abstract]

This article has been cited by other articles:

				G. M. Wieselthaler, M. Riedl, H. Schima, O. Wagner, W. Waldhausl, E. Wolner, A. Luger, and M. Clodi Endocrine function is not impaired in patients with a continuous MicroMed-DeBakey axial flow pump J. Thorac. Cardiovasc. Surg., January 1, 2007; 133(1): 2 - 6. [Abstract] [Full Text] [PDF]

				B. Pieske Reverse remodeling in heart failure - fact or fiction? Eur. Heart J. Suppl., August 1, 2004; 6(suppl_D): D66 - D78. [Abstract] [Full Text] [PDF]

				P. Y. Liu, A. K. Death, and D. J. Handelsman Androgens and Cardiovascular Disease Endocr. Rev., June 1, 2003; 24(3): 313 - 340. [Abstract] [Full Text] [PDF]

				G. S. Kumpati, P. M. McCarthy, and K. J. Hoercher Left ventricular assist device bridge to recovery: a review of the current status Ann. Thorac. Surg., March 1, 2001; 71 (2007): S103 - S108. [Abstract] [Full Text] [PDF]

				P.J. Pugh, K.M. English, T.H. Jones, and K.S. Channer Testosterone: a natural tonic for the failing heart? QJM, October 1, 2000; 93(10): 689 - 694. [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Malcolm Underwood Gebrine El Khoury Martin Goenen Robert Dion Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Noirhomme, P. Articles by Dion, R. Search for Related Content PubMed PubMed Citation Articles by Noirhomme, P. Articles by Dion, R.