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European Journal of Heart Failure 2008 10(12):1208-1214; doi:10.1016/j.ejheart.2008.09.011
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© 2008 European Society of Cardiology

Transcardiac increase in norepinephrine and prognosis in patients with chronic heart failure

Takayoshi Tsutamoto*, Keizo Nishiyama, Hiroshi Sakai, Toshinari Tanaka, Masanori Fujii, Takashi Yamamoto, Masayuki Yamaji and Minoru Horie

Cardiovascular and Respiratory Medicine, Shiga University of Medical Science Tsukinowa, Seta, Otsu 520-2192, Japan

* Corresponding author. Tel.: +81 77 548 2213; fax: +81 77 543 5839. E-mail address: tutamoto{at}belle.shiga-med.ac.jp (T. Tsutamoto).


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Background: No previous study has compared the transcardiac gradient of norepinephrine (NE) and the prognosis of patients with chronic heart failure (CHF).

Aim: To evaluate the prognostic role of the transcardiac gradient of NE in patients with CHF.

Methods: We measured haemodynamic parameters and plasma levels of NE, brain natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP) in the aortic root (AO) and coronary sinus (CS) in 356 consecutive patients with CHF.

Results: During a median follow-up of 3.5 years, 40 patients died. Transcardiac gradients of BNP (273±276 vs. 472±433 pg/mL, p<0.0001), NT-proBNP (417±700 vs. 928±1093 pg/mL, p<0.0001) and NE (114±160 vs. 473±992 pg/mL, p<0.0001) were significantly higher in non-survivors than survivors. After adjustment for clinical variables associated with CHF including haemodynamics and neurohumoral factors, the transcardiac gradient of NE (p<0.0001) and plasma log NT-proBNP (p<0.0001) were independent prognostic predictors. Among 67 patients in whom 123I-metaiodobenzylguanidine (MIBG) could be performed, transcardiac increase in NE was correlated with the washout rate (r=0.398, p=0.0009) and was a superior predictor of mortality than MIBG parameters on stepwise multivariable Cox proportional hazards regression analyses.

Conclusion: The transcardiac increase in NE is an independent and useful prognostic predictor for evaluating the prognosis of CHF patients.

Key Words: Sympathetic nervous activity • Norepinephrine • N-terminal pro brain natriuretic peptide • Prognosis • 123I-metaiodobenzylguanidine

Received May 22, 2008; Revised July 30, 2008; Accepted September 22, 2008


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Abnormal sympathetic nerve activation is an important risk factor for patients with chronic heart failure (CHF) and the plasma norepinephrine (NE) level, a marker of systemic sympathetic nerve activity, has been reported to be a useful prognostic biomarker [1-3]. In particular, cardiac sympathetic nerve activity (CSA) plays an important role in the pathophysiology of CHF [4,5]; indeed, cardiac stores of NE become depleted, neuronal NE release is increased and adrenoreceptors are desensitized in CHF [6-9]. Kaye et al. [5] reported that cardiac NE spillover evaluated by the radiotracer technique was more useful for predicting mortality than plasma NE in patients with moderate to severe CHF. Cardiac imaging with 123I-metaiodobenzylguanidine (MIBG), an analogue of NE, has been used to noninvasively assess sympathetic function [10,11]; and decreased uptake and an increased washout rate of MIBG have been observed in patients with CHF [12,13].

Several previous reports have suggested that cardiac 123I-MIBG imaging is more useful than plasma venous NE for evaluating prognosis, suggesting a greater importance of CSA rather than systemic sympathetic nerve activity [14-17]. We previously reported that the transcardiac gradient of NE significantly correlated with washout rate of MIBG imaging [18], suggesting that the transcardiac gradient of NE is a more reliable biomarker of CSA rather than plasma venous NE. Moreover, carvedilol treatment was reported to be associated with a significant reduction in the transcardiac gradient of NE without any changes of plasma arterial NE in patients with CHF [19]. However, the relationship between the transcardiac gradient of NE and mortality of CHF patients remains unknown.

Plasma levels of brain natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP) are well-established biomarkers of CHF [20-23]. No previous study has compared the transcardiac gradient of NE, BNP and NT-proBNP with the prognosis of CHF. In the present study, we compared the transcardiac gradient of NE, BNP and NT-proBNP and MIBG imaging parameters with the prognosis of CHF in the same population.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Patients
Consecutive symptomatic CHF patients (n=356) undergoing cardiac catheterization were included. Patients with acute myocardial infarction, angina pectoris, congenital heart disease or pacemaker implantation, and those on dialysis therapy were excluded. Aetiology of systolic CHF was ischaemic cardiomyopathy (n=216), dilated cardiomyopathy (n=72), or hypertensive heart disease (n=68). NYHA functional class was evaluated on the day of cardiac catheterization. Informed consent was obtained from all patients for participation in the study, following protocol approval by the Committee on Human Investigation at our institution. This was the same study population as in our previously reported study of 366 patients [24], however 8 patients who could not be followed and 2 patients who died of non-cardiac disease were excluded.

2.2. Study protocol
All patients were premedicated with an oral dose of diazepam (5 mg) and rested in bed in a supine position for at least 20 min. Left-sided cardiac catheterization was performed and blood pressure was measured. Heart rate was monitored by electrocardiography. Blood samples for measurement of plasma norepinephrine (NE), BNP and NT-proBNP were collected simultaneously from the aortic root (AO) and coronary sinus (CS). A 6Fr catheter for blood sampling was positioned in the CS, and the position of the catheter was confirmed as previously reported [18]. Blood samples for the measurement of creatinine were also collected from the AO. Left ventriculography was performed using contrast medium or radioisotope before or at least one week after haemodynamic measurements and blood sampling. Renal function was represented by the estimated glomerular filtration rate (eGFR) according to the Cockcroft-Gault equation.

2.3. Measurement of BNP and NT-proBNP
Samples for the assay of plasma BNP and NT-proBNP concentrations were transferred to chilled disposable tubes containing aprotinin (500 kallikrein inactivator units/mL). The blood samples were immediately placed on ice and centrifuged at 4 °C, and the plasma was frozen in aliquots and stored at –30 °C until assay. Plasma BNP concentrations were measured with a specific immunoradiometric assay for human BNP using a commercial kit (Shionogi, Osaka, Japan) as previously reported [20]. Plasma levels of NT-proBNP were measured using the Elecsys proBNP sandwich immunoassay (Roche Diagnostics, Mannheim, Germany) as previously reported [25]. And plasma NE levels were measured by high-performance liquid chromatography as reported previously [20].

2.4. Cardiac MIBG imaging
Cardiac 123I-metaiodobenzylguanidine (MIBG) imaging could be performed in 67 patients within a week of cardiac catheterization. All patients were injected intravenously with 3 mCi of 123I-MIBG. Images were obtained using a single-head gamma camera with a low-energy collimator (Toshiba GCA-901A). Energy discrimination was provided by a 20% window centered on the 159 keV photopeak. A 5-min static acquisition was performed 15 min (early) and 180 min (delayed) after radioisotope injection as previously reported [16]. On the anterior planar image, a region of interest (ROI) was manually placed over the heart and another ROI was placed over the upper mediastinal area. Using early and delayed images, the heart to mediastinum (H/M) ratio and the washout rate were calculated from the average counts in each ROI by two independent observers. The washout rate was defined as the percentage change in cardiac activity (H) from early to delayed images within the left ventricular area as follows: ([(H)–(M)] early–[(H)–(M)] delayed)/[(H)–(M)] earlyx100(%). Decay correction was not applied. Assessment was done in a blinded fashion by two independent observers with no knowledge of the clinical status or medical therapy of the patients. The interobserver differences in the H/M ratio (delayed) and washout rate were not significant. In our laboratory, the normal values of the H/M ratio (delayed) and washout rate were 2.60±0.24 and 28.0±3.1%, respectively [16].

2.5. Statistical analysis
All results are expressed as the mean±SD. Chi-square test was used to determine differences between groups. Univariate analyses were performed using Student's t test. Differences in mean levels of BNP and NT-proBNP between the two groups were tested by Wilcoxon rank-sum test for paired values and by Mann-Whitney U test for unpaired values with two-tailed p values <0.05. Log BNP and log NT-proBNP were used for correlations and regression models. On multivariable Cox proportional hazard analyses, the main models were adjusted for age, sex, and variables considered to reflect the severity of CHF at baseline and those were associated with mortality on univariate analyses at the p<0.10 level. Multivariable Cox proportional hazard analyses were performed as stepwise regressions with backward elimination. The sensitivity and specificity of the transcardiac gradient of NE and log NT-proBNP for predicting mortality were determined, and receiver operating characteristics curves were constructed. Kaplan-Meier analysis was performed on the cumulative rates of survival stratified into two groups based on the cut-off value of the transcardiac gradient of NE and log NT-proBNP, and the differences between survival curves were analyzed by log-rank test. A value of p<0.05 was considered significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
3.1. Patient characteristics
Table 1 summarizes patient characteristics according to survival. During a median follow-up 3.5 years, 40 patients died. Transcardiac gradients of BNP, NT-proBNP and NE were significantly higher in non-survivors than survivors. There was no difference in baseline treatment between the two groups, except for loop diuretics.


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  		Table 1 Haemodynamic and neurohumoral variables in 356 patients with heart failure according to survival

 
3.2. Univariate and multivariable predictors of mortality — comparison of haemodynamic parameters and neurohumoral factors
Twelve clinical, neurohumoral and haemodynamic variables were analyzed using univariate and stepwise multivariable Cox proportional hazards regression analyses (Table 2). On stepwise multivariable analyses, only a high level of transcardiac increase in NE (p<0.0001) and a high level of plasma log NT-proBNP (p<0.0001) were significant independent predictors even after considering the transcardiac increases in BNP and NT-proBNP (Table 2). Receiver operating characteristic curves of transcardiac increase in NE and NT-proBNP demonstrating mortality risks are shown in Fig. 1. There was no difference in the area under the curve for predicting mortality between the transcardiac increase in NE and NT-proBNP. The cut-off level for transcardiac increase in NE was determined as 108 pg/mL, giving a sensitivity of 65% and specificity of 64%. The cut-off level of NT-proBNP was determined as 796 pg/mL, giving a sensitivity of 72% and specificity of 67%.


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  		Table 2 Univariate and multivariate predictors of mortality — comparison of transcardiac gradient of cardiac natriuretic peptides and norepinephrine

 


Figure 01
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  		Fig. 1 Receiver operating characteristic curves for the ability of the transcardiac increase in norepinephrine ({Delta}NE) and plasma level of N-terminal pro brain natriuretic peptide (NT-proBNP) to predict mortality in patients with chronic heart failure. AUC = area under the curve.

 
3.3. Relationship between cardiac MIBG parameters and transcardiac gradient of norepinephrine and prognosis
The washout rate did not correlate with plasma NE in the AO (r=0.229, p=0.0618) but significantly correlated with the transcardiac increase in NE (r=0.398, p=0.0009) (Fig. 2). The H/M ratio significantly correlated with plasma NE in the AO (r=0.289, p=0.016) and the transcardiac increase in log BNP (r=0.398, p=0.0009) (Fig. 2). The washout rate correlated with the transcardiac increase in log BNP (rs=0.281, p=0.02) and the transcardiac increase in log NT-proBNP (rs=0.260, p=0.033) (Fig. 2). The H/M ratio significantly correlated with the transcardiac increase in log BNP (rs=0.427, p=0.0003) and the transcardiac increase in log NT-proBNP (rs=0.425, p=0.0003) (Fig. 2).


Figure 02
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  		Fig. 2 Relationship between cardiac 123I-metaiodobenzylguanidine (MIBG) parameters and the transcardiac gradient in norepinephrine ({Delta}NE) and N-terminal pro brain natriuretic peptide (NT-proBNP) in patients with chronic heart failure. AO = aortic root, CS = coronary sinus, H/M =heart/mediastinum. {Delta}NE=(CS–AO) norepinephrine.

 
During a median follow-up of 3.8 years, 17 patients died. Among the 67 patients in whom MIBG imaging could be performed, the transcardiac increase in NE was an independent prognostic predictor but washout rate and H/M ratio were not (Table 3).


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  		Table 3 Univariate and multivariate predictors of mortality — comparison of MIBG imaging parameters and neurohumoral factors

 
3.4. Kaplan-Meier lifetime analysis
Patients were divided into four groups based on the cut-off levels for the transcardiac gradient of NE and plasma NT-proBNP, and Kaplan-Meier survival curves were constructed (Fig. 3). The hazard ratio of patients with plasma NT-proBNP<796 pg/mL and transcardiac gradient of NE>108 pg/mL was 5.32 (95% confidence interval, 1.41-20.08) compared to those with plasma BNP<796 pg/mL and transcardiac gradient of NE<108 pg/mL for mortality (p=0.013). The hazard ratio of patients with plasma NT-proBNP>796 pg/mL and transcardiac gradient of NE>108 pg/mL was 14.32 (95% confidence interval, 4.21-20.08) compared to those with plasma NT-proBNP<796 pg/mL and transcardiac gradient of NE<108 pg/mL for mortality (p<0.0001).


Figure 03
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  		Fig. 3 Kaplan-Meier survival curves for heart failure patients stratified into four groups based on cut-off levels of plasma N-terminal pro brain natriuretic peptide (NT-proBNP) and the transcardiac gradient in norepinephrine ({Delta}NE).

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
This study showed, for the first time, that the transcardiac gradient of NE is an independent and useful prognostic predictor for evaluating the prognosis of CHF patients even after considering the transcardiac increases in BNP and NT-proBNP. These findings suggest that CSA plays an important role in the pathophysiology of CHF independent of haemodynamic overload and that the transcardiac gradient of NE is a more reliable biomarker of CSA rather than the peripheral venous NE level. Indeed, previous studies including ours showed that the parameters of cardiac MIBG imaging are more useful for predicting mortality than plasma venous NE and provide important prognostic information independent of plasma BNP levels [16,26,27]. In addition, in the present study the transcardiac increase in NE was more useful for predicting mortality than MIBG parameters, suggesting that this is a useful biomarker of CSA in patients with CHF.

Gilbert et al. [19] measured the plasma levels of NE in CS and in the systemic artery before and after 4 months of metoprolol or carvedilol treatment in placebo-controlled trials and found that compared with the placebo group, carvedilol treatment was associated with a significant reduction in transcardiac NE. Furthermore, compared with changes in the metoprolol group, carvedilol was associated with a strong trend towards a reduction of NE in the CS. In the present study, the transcardiac NE gradient was slightly lower in the 149 patients on β blocker treatment (mainly carvedilol) than in patients not receiving β blockers (113±152 vs. 183±476 pg/mL, p=0.08). In the Carvedilol Or Metoprolol European Trial (COMET) [28], a randomized trial of 3029 patients with CHF, carvedilol reduced mortality by 17% relative to metoprolol (p<0.0017). Taken together with our previous findings [16,18] and those by Gilbert et al. [19], it may be useful to measure plasma NE levels in the CS and AO in patients with moderate to severe CHF.

Beyond β blocker therapy, cardiac resynchronisation therapy (CRT) has been shown to reduce mortality in CHF patients who were already receiving standard medication [29]. However, it is not easy to distinguish responders to CRT from non-responders. Recently, Burri et al. [30] reported that responders showed a lower MIBG washout rate at follow-up compared with that in non-responders. Compared to MIBG imaging, blood sampling and measurement of NE and BNP from the CS and systemic artery are relatively easy and may be useful in identifying CHF patients who are candidates for CRT.

In the present study, a high level of plasma NT-proBNP was a significant independent predictor even after considering transcardiac increases in BNP and NT-proBNP. The reason why plasma NT-proBNP was more useful for predicting mortality than transcardiac increase in NT-proBNP is not easy to explain. In previous studies including ours, parameters such as left ventricular end-diastolic pressure, left ventricular ejection fraction, left ventricular mass index, anaemia (haemoglobin) and renal function (eGFR), were confirmed as prognostic markers respectively influencing the plasma levels of NT-proBNP [25]; therefore, a single measurement of NT-proBNP in plasma may be a stronger prognostic indicator than haemodynamics and the transcardiac increases in BNP and NT-proBNP in CHF patients [31]. In contrast, not peripheral NE but the transcardiac increase in NE was another important prognostic predictor in this study, suggesting the important role of CSA in CHF.

There are several limitations in this study. First, we did not measured coronary blood flow. Second, the myocardial or interstitial NE concentration, which is a rational biomarker of CSA, cannot be estimated simply by the transcardiac increase in NE and coronary blood flow [32,33]. Further studies are needed to compare the prognostic value of the transcardiac increase in NE with cardiac NE spillover, which can be evaluated by the radiotracer method and by measuring coronary sinus blood flow. A third limitation is the small number of deaths in the study; however, BNP and NT-proBNP were measured in the AO and CS, and MIBG imaging was also performed in the present study.

In conclusion, the transcardiac gradient of NE is an independent and useful prognostic predictor for evaluating the prognosis of CHF patients even after considering the transcardiac increases in BNP and NT-proBNP and MIBG imaging parameters.


   Acknowledgements
 
We wish to thank Yohko Watanabe for excellent technical assistance. We also express thanks to Mr. Daniel Mrozek for assistance in preparing the manuscript. This study was supported by a Grant-in-Aid for Scientific Research in Japan.


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

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CHAPTER 23 Heart Failure
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