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European Journal of Heart Failure 2001 3(6):693-697; doi:10.1016/S1388-9842(01)00184-2
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© 2001 European Society of Cardiology

Relationship between cardiac metaiodobenzylguanidine uptake and hemodynamic, functional and neurohormonal parameters in patients with heart failure

Paul A.R. de Milliano*, Berthe L.F. van Eck-Smit, Pieter A. van Zwieten, Andre C. de Groot, Jan G.P. Tijssen and Kong I. Lie

Departments of Cardiology, Nuclear Medicine and Biostatistics, ziekenhuis Hilversum, Hilversum and the Academic Medical Center Amsterdam, The Netherlands

* Corresponding author. E-mail address: pardemilliano{at}wxs.nl (P.A. de Milliano).


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Background: Sympathetic activation plays a pivotal role in heart failure attributing to the disease process and symptoms of the patient. Myocardial sympathetic activity can be visualized using radioiodinated metaiodobenzylguanidine 123I-MIBG, a structural analogue of norepinephrine (NE).

Aim of the study: We investigated whether a relation exists between myocardial MIBG uptake and different functional, hemodynamic and neurohormonal parameters in patients with chronic heart failure.

Methods and results: The study comprised 52 patients with stable congestive heart failure functional class II or III and left ventricular ejection fractions of <35%. The heart/mediastinum ratio (H/M ratio) was calculated to quantify myocardial MIBG uptake. A significant correlation was found between peak oxygen consumption and maximal exercise duration as exercise parameters and H/M ratio of MIBG (R, respectively, 0.36 and 0.4, P<0.05). From all other measured parameters, only plasma NE showed a significant correlation with the H/M ratio of MIBG.

Conclusion: Cardiac sympathetic activity, as measured by myocardial MIBG uptake, is correlated with peak exercise parameters.

Key Words: Heart failure • Norepinephrine • Nervous system • Autonomic • Exercise

Received May 10, 2000; Revised March 5, 2001; Accepted May 9, 2001


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Heart failure frequently leads to progressive exercise intolerance. Several factors may attribute to this reduced exercise capacity including a decreased cardiac output, changes in skeletal muscle metabolism, wasted skeletal muscle, reduced baroreflex sensitivity, angina threshold and chronic sympathetic overactivity. The general activation of sympathetic function plays a key role in the syndrome of heart failure and can initially be considered as compensation but with progression of the disease it becomes pathological and even aggravates the disease process.

Radioiodinated metaiodobenzylguanidine (123I-MIBG), an analogue of norepinephrine can be used to visualize and quantify myocardial sympathetic activity and integrity. Reduced myocardial MIBG uptake has been demonstrated in heart failure and a correlation exists between severity of disease and MIBG uptake [1,2]. Recently, Atsumi showed a correlation between exercise capacity and myocardial MIBG uptake [3]. The purpose of the present study was to investigate the relation between myocardial MIBG uptake and different functional, hemodynamic and neurohormonal parameters in patients with chronic heart failure.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Study patients
The study was approved by the review board and the ethics committee of both participating institutions. Written informed consent was obtained from all patients before they entered the study. The investigation conforms with the principles outlined in the Declaration of Helsinki.

We examined 52 patients with a history of chronic symptomatic heart failure, NYHA functional class II or III and an ejection fraction of <35% as assessed by radionuclide ventriculography. Both ischemic and non-ischemic cardiomyopathies were included. Patients were classified as ischemic if they had a history of a documented myocardial infarction and/or coronary angiography showed significant coronary artery disease.

Inclusion required stable disease for at least 4 weeks without change in medication before measurement of all functional, hemodynamic and neurohormonal parameters and myocardial MIBG uptake. Exclusion included obstructive airway disease, inability to exercise for other reasons than heart failure, objective signs of ischemia and angina pectoris as limiting factor during exercise.

2.2. Functional parameters
The 6-min walk test was conducted using a pre-defined course in the corridors of our hospital with small distance markers on the wall. Patients walked at their own pace and were allowed to stop during the test but were instructed to resume walking as soon as they were able to do so. They were unaware of the distance markers. A study nurse accompanied them but did not attempt to influence the patient. After 6 min they stopped walking and the total distance walked was measured. The course can be entered at different places to avoid patient bias when the test is repeated. A previous study with this course showed an excellent reproducibility of the test in our hospital.

Peak oxygen consumption was measured on a bicycle ergometer according to previous defined standards.

For the quality of life assessment the Minnesota living with heart failure questionnaire was used [4].

2.3. Neurohormones
Blood samples for plasma catecholamines and atrial natriuretic factor (ANP) were drawn after 30 min of rest in supine position. An indwelling catheter in the antecubital vein inserted before the resting period was used. Bloodsamples were transferred immediately to ice-chilled tubes. The plasma was separated through centrifugation at 4°C and stored at –70°C until assay. Plasma NE concentration was determined by high performance liquid chromatography and electrochemical detection, after purification on Biorex 70 and concentration by solvent extraction. Atrial natriuretic peptide was determined by radio-immunoassay (Nichols Institute Diagnostics, Wychen, the Netherlands).

2.4. 123I-MIBG imaging
123I-MIBG imaging was performed in the morning 1 h after 100 mg potassium orally to block thyroid uptake of free 123I. 123I-MIBG; (185 MBq Cygne BV, Technical University Eindhoven, the Netherlands) was injected intravenously. Images were obtained 3 h after injection (planar imaging, medium-energy collimator). A 20% energy window centered on the 159-keV photopeak of 123I was used. A region of interest was manually drawn around the left ventricle. Mediastinum activity was measured using a 7x7-pixel region of interest over the upper mediastinum. Cardiac MIBG uptake was quantified by calculating the heart to mediastinum ratio (mean counts per pixel in the heart divided by those in the mediastinum).

2.5. Statistical methods
Numeric values are expressed as means±standard deviation. Correlations were calculated for all continuous variables. Pearson's correlations were calculated using SPSS and considered significant at the 0.05 level (2-tailed).


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
Initially, 52 patients were included. One patient was excluded from all analysis because (nor)epinephrine concentrations were far beyond the normal range. In retrospect, there was a highly significant uptake of MIBG in the renal region, suggesting a pheochromocytoma. His progressive heart failure was probably related to this entity. He died shortly after inclusion in this study. Baseline characteristics are summarized in Table 1. Results of all measured parameters and their correlation with MIBG uptake are summarized in Table 2. Mean H/M ratio of MIBG uptake was 1.8±0.45.


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  		Table 1 Baseline characteristics

 


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  		Table 2 Correlation between measured parameters and H/M ratio of MIBG

 
A significant correlation was found between the H/M ratio and two clinically used exercise parameters: peak oxygen consumption and maximal exercise duration (R, respectively, 0.36 and 0.4, P<0.05, Figs. 1 and 2). This correlation was not found between total distance during the 6-min walking test and MIBG uptake (R=0.2, P=0.2). No correlation could be found between heart rate, blood pressure, left ventricular ejection fraction, end-diastolic diameter and quality of life assessment and MIBG uptake. From the three measured neurohormones, only plasma NE showed a significant correlation with MIBG uptake (R=–0.35, P=0.01). In addition, a correlation was found between total distance during the 6-min walking test and peak oxygen consumption (R=0.7, P=0.001) and between the total distance during the 6-min walking test and duration of maximal exercise testing during peak VO2 testing (R=0.7, P=0.001). Left ventricular ejection fraction was not correlated to any exercise parameter.


Figure 1
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  		Fig. 1 Regression of heart/mediastinum ratio of MIBG uptake vs. peak oxygen consumption (P<0.05).

 


Figure 2
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  		Fig. 2 Regression of heart/mediastinum ratio of MIBG uptake vs maximal exercise duration (P<0.05).

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
Our study demonstrates a correlation between myocardial MIBG uptake and two important exercise parameters: peak oxygen consumption and maximal exercise duration. These results extend the observations of two recently published studies that also demonstrated a significant correlation between myocardial MIBG uptake and peak oxygen consumption in patients with mild to moderate heart failure [2,3]. In contrast, exercise duration during submaximal testing was not correlated to cardiac MIBG uptake.

4.1. Sympathetic activity and peak VO2.
Exercise intolerance resulting in exertional fatigue and dyspnea is a key feature in patients with heart failure. Different mechanisms have been identified to explain these symptoms. First, there are cardiac limitations as a result of a decreased cardiac output. However, from clinical practice it is known that cardiac factors are not the sole mechanism by which exertional symptoms can be explained as demonstrated by the fact that a correlation between left ventricular ejection fraction and exercise capacity has never been demonstrated. Second, in addition to other peripheral factors [5], increased muscle sympathetic activity has been correlated to reduced exercise tolerance [6]. Results from our study and others [2,3] suggest, however, that the correlation between increased sympathetic tone and exercise impairment is not restricted to sympathetic tone at the level of the peripheral muscle but can also be demonstrated for cardiac sympathetic tone. It might well be possible that local and systemic increase of sympathetic activity (including for example baroreflex impairment) contributes to the observed decrease in exercise tolerance.

The fact that myocardial sympathetic activation as measured by MIBG uptake is correlated to exercise capacity in contrast to several hemodynamic and functional parameters emphasizes the role of neurohumoral activation in heart failure.

There is another explanation for the observed correlation between peak VO2 and myocardial MIBG uptake because both parameters have been related to disease severity and prognosis [2,7–9]. The relation between peak VO2 and cardiac MIBG uptake thus represents two different parameters of the same phenomenon: disease severity without direct correlation. It cannot be elucidated from our data whether this hypothesis is true.

4.2. Maximal vs. submaximal exercise testing
In contrast to peak exercise parameters (peak exercise duration and peak VO2), the distance ambulated during the 6-min walk test could not be correlated to cardiac MIBG uptake.

The 6-min walk test is an objective measure of submaximal exercise capacity in congestive heart failure and has been correlated to both to prognosis and peak VO2 [10–12]. It reflects functional capacity during daily activity probably better than maximal exercise testing in laboratory conditions. Although the distance walked during the 6-min walk test correlated to both peak VO2 and maximal exercise duration in our study, no correlation could be found between the results of the 6-min walk test and myocardial MIBG uptake. The reason for this is not immediately obvious and cannot be clarified from our data. In line with this observation is the fact that the assessment of quality of life and functional class were not correlated to cardiac MIBG uptake. Both quality of life assessment and functional class reflect functional capacity during normal daily life as is the case with the distance ambulated during the 6-min walk test.

In conclusion, the results from our study indicate that a correlation exists between cardiac sympathetic activity as measured by myocardial MIBG uptake and peak exercise parameters (maximal exercise duration and peak oxygen consumption).

4.3. Study limitations
This study was conducted before β-blocker treatment became part of routine clinical practice in heart failure patients. Although β-blockers have an effect on sympathetic activity and myocardial MIBG uptake, the effect of β-blockers on exercise capacity seems to be marginal. It can, however, not be predicted whether the observed correlation between peak VO2 and maximal exercise duration and myocardial MIBG also applies to patients with heart failure treated with β-blockers.


   Acknowledgements
 
This research was supported in part by unrestricted grants from AstraZeneca, Zoetermeer, Ziekenhuis Hilversum, Hilversum and The Academic Medical Center, Amsterdam.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

  1. Wakasugi S., Inoue M., Tazawa S. Assessment of adrenergic neuron function altered with progression of heart failure. J Nucl Med (1995) 36:2069–2074.[Abstract/Free Full Text]
  2. Cohen-Solal A., Esanu Y., Logeart D., et al. Cardiac metaiodobenzylguanidine uptake in patients with moderate chronic heart failure: relationship with peak oxygen uptake and prognosis. J Am Coll Cardiol (1999) 33:759–766.[Abstract/Free Full Text]
  3. Atsumi H., Takeishi Y., Fujiwara S., Tomoike H. Cardiac sympathetic nervous disintegrity is related to exercise intolerance in patients with chronic heart failure. Nucl Med Commun (1998) 19:451–456.[Web of Science][Medline]
  4. Rector T.S., Cohn J.N. Assessment of patient outcome with the Minnessota Living with Heart Failure questionaire: reliability and validity during a randomized, double blind, placebo controlled trial of pimobendan. Am Heart J (1992) 1024:1017–1025. with the Pimobendan Multicenter Research Group.
  5. Clark A., Poole Wilson P., Coats A. Exercise limitations in chronic heart failure: the central role of the periphery. J Am Coll Cardiol. (1997) 28:1092–1102.[CrossRef][Web of Science]
  6. Notarius C., Ando S., Rongen G., Floras J.S. Resting muscle sympathetic nerve activity and peak oxygen uptake in heart failure and normal subjects. Eur Heart J. (1999) 20:880–887.[Abstract/Free Full Text]
  7. Merlet P., Valette H., Dubois-Rande J.L., et al. Prognostic value of cardiac metaiodobenzylguanidine imaging in patients with heart failure. J Nucl Med (1992) 33:471–477.[Abstract/Free Full Text]
  8. Nakata T., Miyamoto K., Doi A., et al. Cardiac sympathetic nerve function, metaiodobenzylguanidine, prognosis: cardiac death prediction and impaired cardiac sympathetic innervation assessed by MIBG in patients with failing and nonfailing hearts. J Nucl Cardiol (1998) 5:579–590.[CrossRef][Web of Science][Medline]
  9. Opasich C, Pinna GD, Bobbio M et al. Peak exercise oxygen consumption in chronic heart failure: toward efficient use in the individual patient. J Am Coll Cardiol 1998, 766–75.
  10. Bittner V., Weiner D.H., Yusuf S. for the SOLVD investigators. Prediction of mortality and morbidity with a 6-minute walk test in patients with left ventricular dysfunction. J Am Med Assoc (1993) 270:1702–1707.[Abstract/Free Full Text]
  11. Cahalin L.P., Mathier M., Semigran M.J., Dec W., DiSalvo T.G. The six-minute walk test predicts peak oxygen uptake and survival in patients with advanced heart failure. Chest (1996) 110:325–332.[CrossRef][Web of Science][Medline]
  12. Zugck C., Kruger C., Durr S., et al. Is the 6-minute walk test a reliable substitute for peak oxygen uptake in patients with dilated cardiomyopathy? Eur Heart J. (2000) 21:540–549.[Abstract/Free Full Text]

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This Article
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