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Vol. 58. Issue 11.
Pages 1273-1277 (November 2005)
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Vol. 58. Issue 11.
Pages 1273-1277 (November 2005)
DOI: 10.1016/S1885-5857(06)60414-3
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Neurohormones and Cytokines in Heart Failure. Correlation With Coronary Flow Reserve
Neurohormonas y citocinas en la insuficiencia cardíaca. Correlación con la reserva de flujo coronario
Isabel Coma-Canellaa, Alfonso Macíasa, Nerea Varob, Alfonso Sánchez Ibarrolac
a Servicio de Cardiología, Clínica Universitaria, Facultad de Medicina, Universidad de Navarra, Pamplona, Spain.
b Servicio de Bioquímica, Clínica Universitaria, Facultad de Medicina, Universidad de Navarra, Pamplona, Spain.
c Servicio de Inmunología, Clínica Universitaria, Facultad de Medicina, Universidad de Navarra, Pamplona. Spain.
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Tables (6)
TABLE 1. Patient Characteristics*
TABLE 2. Echocardiographic Diagnosis and Variables*
TABLE 3. Neurohormone Levels*
TABLE 4. Cytokine Levels*
TABLE 5. Myocardial Flow and Coronary Flow Reserve Measured by Positron Emission Tomography*
TABLE 6. Correlation Between Reserve and Neurohormones and Cytokines*
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Introduction and objectives. In heart failure, the coronary flow reserve (CFR) measured by positron-emission tomography (PET) is reduced. As neurohormone and cytokine levels are also altered in patients with the condition, our aim was to determine whether there is a correlation between CFR and neurohormone and cytokine levels. Patients and method. The study included 40 patients with heart failure but without ischemic heart disease. Myocardial blood flow was measured by PET using nitrogen-13 ammonia at baseline and during adenosine triphosphate (ATP) infusion. The CFR was calculated for each patient. In addition, levels of the following were determined: norepinephrine, endothelin-1, angiotensin-II, atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), tumor necrosis factor-alpha, interleukin (IL)-1β, soluble IL-2 receptor, and IL-6. Results. All factors levels were elevated above reference values. The levels of all cytokines, except IL-1β, were also elevated. There was a significant negative correlation between CFR and the levels of several neurohormones: ANP (r=­0.476), BNP (r=­0.442), and IL-6 (r=­0.509). Conclusions. In heart failure, the decrease in CFR is correlated with increases in the levels of certain neurohormones (i.e., ANP and BNP) and cytokines (i.e., IL-6), with vasodilatory effect. These increases are probably compensatory mechanisms insufficient to correct the endothelial dysfunction present in these patients.
Heart failure
Coronary flow reserve
Introducción y objetivos. La reserva del flujo coronario (RFC) medida con tomografía por emisión de positrones (PET) está disminuida en la insuficiencia cardíaca. Puesto que las neurohormonas y las citocinas también presentan modificaciones en estos pacientes, pretendemos comprobar si hay correlación entre la RFC y los valores de neurohormonas y citocinas. Pacientes y método. Se estudió a 40 pacientes diagnosticados de cardiopatía no isquémica e insuficiencia cardíaca. El flujo miocárdico (FM) se midió mediante PET y N-13 amonio: en condiciones basales y durante la infusión de trifosfato de adenosina (ATP). En cada uno se calculó la RFC. En todos se determinaron la noradrenalina, la endotelina-1, angiotensina II, el péptido natriurético auricular (ANP) y cerebral (BNP), el factor de necrosis tumoral alfa, la interleucina (IL)-1β y el receptor soluble de IL-2 e IL-6. Resultados. Todas las neurohormonas medidas tuvieron valores superiores a los de referencia. Las citocinas medidas también estuvieron elevadas, excepto la IL-1β. Se encontró una correlación negativa significativa entre la RFC y los siguientes factores: ANP (r = ­0,476), BNP (r = ­0,442) e IL-6 (r = ­0,509). Conclusiones. En la insuficiencia cardíaca, la disminución de la RFC se correlaciona con el aumento de determinadas neurohormonas (ANP, BNP) y citocinas (IL-6), de efecto vasodilatador. Se trata, probablemente, de mecanismos de compensación insuficientes ante la disfunción endotelial que presentan estos enfermos.
Palabras clave:
Insuficiencia cardíaca
Reserva de flujo coronario
Full Text


In a previous study,1 we demonstrated for the first time that the coronary flow reserve (CFR), measured by positron emission tomography (PET), is reduced in nonischemic heart failure, regardless of the etiology. Moreover, in those patients presenting a worse functional class, the reserve is also more markedly affected.

On the other hand, a number of studies show that heart failure is associated with increases in the levels of certain neurohormones and cytokines,2-11 including norepinephrine, angiotensin II, endothelin 1, atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), interleukin (IL)-1, IL-6, soluble IL-2 receptor, and tumor necrosis factor-alpha (TNF-α). The extent of these increases is generally related to the prognosis.

The objective of this study was to establish the possible correlation between PET-measured CFR and neurohormone and cytokine levels.



The study included 40 consecutive patients (mean age, 63±11 years; 27 men), 30 outpatients and 10 inpatients being treated in the cardiology service. The inclusion criteria were age over 18 years, nonischemic heart disease and a history of heart failure. Those patients presenting infection, chronic inflammatory disease, malignant tumor and/or renal failure (serum creatinine greater than 2 mg/dL) were excluded, as were women who might be pregnant. The study was approved by the ethics committee of the center and all the patients signed an informed consent form prior to their inclusion.


All the patients were assessed on the basis of a complete clinical history, physical examination, routine analyses (differential cell count, systematized urinalysis and blood chemistry), 12-lead electrocardiogram and echocardiogram. All of them had undergone coronary angiography within the preceding 6 months.


At the time of the study, the patients were being treated with angiotensin-converting enzyme inhibitors, angiotensin II receptors, digitalis, diuretics and beta-blockers. Each patient was taking several of these drugs and some patients were receiving all of them.

Positron Emission Tomography

Eighty studies were performed in the 40 patients. In each, PET was carried out with 13N ammonium at baseline (resting) and immediately after infusion of adenosine triphosphate to induce stress.1

Neurohormones and Cytokines

Venous blood samples were taken after an overnight fast and 30 minutes of rest in a supine position. All the collection tubes contained the anticoagulant EDTA. The samples were centrifuged for 30 minutes and the plasma stored at ­80ºC for subsequent analysis.

The neurohormones were determined by radioimmunoassay according to the instructions of the manufacturer (IRMA, CIS bio international, France). The normal values for our laboratory, established previously with a control group, are: norepinephrine, 273±102 pg/mL; endothelin-1, 1.76±0.8 pg/mL; angiotensin II, 6.1±3 pg/mL; ANP, 19±5 pg/mL and BNP, 17.4±4.8 pg/mL. The cytokines were determined by enzyme immunoassay following the instructions of the manufacturer (RD System, Abingdon, UK). The normal values are: TNF-α, 3.1±0.6 pg/mL; IL-1β, 0.5±0.4 pg/mL; soluble IL-2 receptor, 1007±250 pg/mL, and IL-6, 1.77±0.9 pg/mL.

Statistical Analysis

The study data were loaded on a SPSS database. The descriptive statistics were the mean and the standard deviation. The correlation between the quantitative variables was examined using Pearson's coefficient when the distribution was normal and the Spearman coefficient when it was not. A P value of less than .05 was considered to indicate statistical significance.


Characteristics of the Patients Studied

Table 1 shows the demographic characteristics and cardiovascular risk factors of the patients enrolled in the study. The diagnoses and major echocardiographic variables appear in Table 2.

Neurohormones and Cytokines

The mean values of the neurohormones and cytokines measured are displayed in Tables 3 and 4, respectively. Table 3 shows that the levels of all the neurohormones measured were elevated with respect to the reference values, while the results in Table 4 demonstrate that all the cytokines measured, except for IL-1β, were also higher than their reference values.

Coronary Flow Reserve Measured by Positron Emission Tomography

These values are summarized in Table 5. Taking into account the fact that the normal CFR in individuals of an age similar to that of the patients included in this study is 3±0.73,12 this variable is seen to be considerably reduced in the study population.

Correlation Between Coronary Flow Reserve and Neurohormone and Cytokine Levels

As can be seen in Table 6, there was a significant negative correlation between CFR and ANP, BNP, and IL-6. No correlation was found with the remaining variables.



The present study demonstrates that heart failure is associated with neurohormonal activation, with increases in all the variables measured with respect to the reference values. Norepinephrine showed the least change, a fact that might be attributable to the drugs taken by the patients, some of which (the beta-blockers) inhibit the sympathetic nervous system. Angiotensin II is increased despite the fact that most of the patients were being treated with angiotensin-converting enzyme receptors or ARBs. Without these drugs, the increase would probably have been greater.


Among the cytokines determined in the patients, TNF-α, IL-6 and soluble IL-2 receptor were higher than their reference values. These results agree with those reported by most authors, who have found heart failure to be associated with neurohormonal activation and elevated cytokine concentrations.2-11

However, there was no increase in IL-1β. This cytokine plays an important pathophysiological role in the origin and development of heart failure but, in contrast to other cytokines, its actions are focused basically on the myocardium.13 This fact would explain the failure of the majority of the studies,14 including ours, to demonstrate elevated IL-1β values in peripheral blood.

IL-6 is the cytokine that showed the most marked increase in our study, a circumstance that agrees with a large number of reports that demonstrate a fundamental role for IL-6 in heart failure.2,9,15,16

Coronary Flow Reserve Measured by Positron Emission Tomography in Heart Failure

Patients with heart failure in the absence of ischemic heart disease have reduced CFR. The most marked decrease is detected in individuals in New York Heart Association functional class III-IV,1 who present significant differences with respect to those who are in functional class I. In this study, we present the overall mean values for the total group of 40 patients, without dividing them into subgroups, in order to simplify the data.

Correlation Between Coronary Flow Reserve, Neurohormones, and Cytokines

The present study demonstrates a significant negative correlation between PET-measured CFR and certain variables (ANP, BNP, and IL-6) in patients with nonischemic heart failure. We expected to observe a negative correlation between the CFR and those neurohormones and cytokines, such as norepinephrine, angiotensin II, endothelin-1, and TNF-α, that produce vasoconstriction, but this was not the case.

Natriuretic peptides are known to have both arterial and venous vasodilatory properties and, thus, they exert a compensatory effect in heart failure.17 IL-6 enhances endothelium-dependent vasodilation, while it induces myocardial dysfunction. This suggests that its local production regulates resistance and vascular permeability in these patients.18 It is a well-known fact that heart failure is associated with endothelial dysfunction,19 with vasoconstriction of large and small vessels of the myocardium20 and the peripheral arteries.21 This may be due not only to sympathetic activation and increases in endothelin-1 and TNF-α, but to other mechanisms, such as the augmented production of oxygen free radicals.19,22,23 The increases in ANP, BNP and IL-6 may be compensatory mechanisms to counteract the vasoconstriction owing to a number of causes.

To the best of our knowledge, the correlation between PET-measured CFR and neurohormone and cytokine levels in heart failure has not been evaluated previously. As is the case in so many processes, some compensatory mechanisms prove to be deleterious; one such mechanism is the increase in IL-6, which can intensify the severity of ventricular dysfunction and, thus, of heart failure.


The major limitation of this study is the small number of patients included, owing to the difficulty associated with PET, which is a complex and costly technique. Thus, it can not be performed in as many patients as would be desirable. The data presented here do not allow to know whether or not the evaluation of a greater number of cases would enable the detection of a greater number of significant relationships than those observed in this study.


The reduction of the CFR observed in heart failure correlates with increases in certain neurohormones (ANP and BNP) and cytokines (IL-6), all of which have vasodilatory effects. This circumstance suggests that they are probably involved in compensatory mechanisms that prove to be insufficient against the multifactorial endothelial dysfunction presented by these patients.

ANP: atrial natriuretic peptide.
BNP: brain natriuretic peptide.
CFR: coronary flow reserve.
IL: interleukin.
PET: positron emission tomography.
TNF-α: tumor necrosis factor-alpha.

This study was financed by a grant from the FIS, Spain.

Correspondence: Dra. I. Coma-Canella.
Departamento de Cardiología. Clínica Universitaria.
Avda. de Pío XII, 36. 31008 Pamplona. España.

Received February 7, 2005.
Accepted for publication June 22, 2005.

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Revista Española de Cardiología (English Edition)

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