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European Journal of Heart Failure 2006 8(6):599-608; doi:10.1016/j.ejheart.2005.11.015
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© 2005 European Society of Cardiology

Tei index and neurohormonal activation in patients with incident heart failure: Serial changes and prognostic value

Kirsten V. Mikkelsena,*, Jacob E. Møllera, Peter Bieb, Henrik Rydec, Lars Videbæka and Torben Haghfelta

a Department of Cardiology, Odense University Hospital Odense, Denmark
b Department of Physiology and Pharmacology, Institute of Medical Biology, University of Southern Denmark Odense, Denmark
c Department of Internal Medicine and Cardiology, Slagelse Hospital Slagelse, Denmark

* Corresponding author. Langelinie 119, DK-5230 Odense M, Denmark. Tel.: +45 65412620. E-mail address: kvm{at}nameplanet.com (K.V. Mikkelsen).


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
Background: Natriuretic peptides and Tei index are useful indices for risk stratification in advanced left ventricular dysfunction (LVD). Their role in early stages is less clear.

Aims: In relation to first diagnosis of LVD to assess the relation of plasma B-type-natriuretic peptide (NT-proBNP) with Tei index, assess serial changes in indices, and to assess the value of indices to predict functional status.

Methods: Doppler echocardiography and neurohormonal analysis were performed (n = 150). NYHA class was registered.

Results: Tei index correlated with p-NT-proBNP (r = 0.75, p < 0.0001), and changes in indices correlated (r = 0.36, p = 0.001) in LVD (n = 80). No functional improvement (n = 47) was related to a median increase in Tei index (–0.2, –0.16; 0.09); an improvement (n = 31) to a reduction (0.06; –0.19; 0.35), p = 0.02. In the group with functional improvement, more patients had ≥ 30% reduction in p-NT-proBNP (75% vs. 45%, p < 0.01). Addition of NT-proBNP or Tei index to a clinical model, of no functional improvement, improved log-likelihood X2 from 9.32 to 20.18 (p = 0.001) and 20.67 (p = 0.001).

Conclusion: Tei index and p-NT-proBNP demonstrated a fair correlation. Unimproved NYHA class was related to progressive LVD and might be identified by monitoring Tei index or p-NT-proBNP. Advanced LVD and high pre-treatment p-NT-proBNP levels indicated a potential of improvement in functional status.

Key Words: Heart failure • Prognosis • Functional class • Tei index • Natriuretic peptides

Received March 4, 2005; Revised August 1, 2005; Accepted November 28, 2005


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
Heart failure (HF) with left ventricular systolic dysfunction (LVSD) is characterized by neurohormonal activation [1] and considerable morbidity and mortality [2,3]. From epidemiological studies, it has become apparent that symptomatic HF often is presently concomitant with apparently preserved left ventricular (LV) systolic function, especially among women and elderly patients [2,4,5]. Although a low ejection fraction (EF) beyond any doubt is an important prognostic factor, it may be of little prognostic value in early cases of HF, especially in populations where the prevalence of HF with preserved systolic function (HFPSF) is high. Recent studies have demonstrated a considerable prognostic potential of assessment of neurohormonal activation by measuring cardiac B-type natriuretic peptide (BNP and N-terminal proBNP (NT-proBNP)) in patients with predominantly systolic HF (SHF) [6-9]. Also, increased concentrations of BNP and NT-proBNP have been detected in HFPSF [10,11]. However, little is known of the prognostic value of BNP and of the role of BNP in monitoring disease progression in HFPSF and in incident cases of SHF. Another promising tool for risk stratification in HF and ischaemic heart disease is the Doppler echocardiographic Tei index, which combines indices of contraction and relaxation in an overall index of LV function [12]. The index correlates well with symptomatic status and the severity of SHF [13-15]. However, little is known of the prognostic value of the index in early stages of HF and about its association to neurohormonal activation.

In the present study, we studied patients with suspected incident HF. In this setting, we hypothesised that Tei index would be a sensitive and a readily accessible estimate of LV function that could be useful for serial assessment of LV function. As a reference, B-type natriuretic peptide was chosen as a sensitive biochemical marker of LVD. Thus, we sought in the present study to assess the relation of NT-proBNP with the Doppler echocardiographic Tei index, and to assess their association with functional class and quality of life (QOL). Furthermore, serial measurements were done to assess the relation of changes in the indices, and to assess the prognostic value of the indices to predict functional status and QOL 1 year after first diagnosis of HF.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Conclusion
 References
 
2.1. Study population
One hundred and fifty ambulatory patients referred to the institution's HF Clinic due to suspected but undiagnosed HF were consecutively enrolled in the study. All patients were referred from primary care physicians. To increase pretest probability of HF, and to reduce potential variability in neurohormonal activation, patients with a history of valvular heart disease, chronic pulmonary arterial hypertension, anaemia, renal, hepatic or thyroid dysfunction, acute coronary syndrome or coronary revascularisation less than 3 months prior to referral, or chronic obstructive pulmonary disease were excluded. Patients receiving medical treatment with diuretics, ACE-inhibitors, angiotensin II receptor blockers, β-blockers, spironolactone or digoxin were also excluded. Sinus rhythm and an adequate echocardiographic window were mandatory.

The HF diagnosis was based on history, physical examination and chest X-ray. An abnormal echocardiogram was mandatory although Tei index was not used in diagnosis of HF. The results of the neurohormone analyses were blinded until termination of follow-up.

The study was approved by the regional scientific ethics committee. All patients gave informed written consent. Of referred patients, 1% refused consent and 8% were excluded due to contraindications.

2.2. Echocardiography
Echocardiography was performed by a single investigator (KVM) in the morning to exclude potential influence of circadian variation. A Hewlett Packard Sonos 5500 ultrasound instrument with a 3.25-MHz transducer was used. Three to five cardiac cycles were stored digitally. Echocardiography was performed at inclusion and after 6 and 12 months.

2.2.1. Two-dimensional echocardiography
LV dimensions were measured as proposed by the American Society of Echocardiography [16]. LV systolic function was estimated using EF by Simpson's modified biplane method [16]. Endocardial border detection was enhanced by using second harmonic imaging.

2.2.2. Doppler echocardiography
Transmitral flow [17,18] was recorded from the apical four-chamber view with a 1-2 mm sample volume placed at the tips of the mitral valve leaflets during diastole. Peak E velocity (cm/s), peak A velocity (cm/s), E/A ratio, deceleration time (DT) (ms) and A wave duration (ms) were obtained. Isovolumetric relaxation time (IVRT) (ms) was measured as the time from cessation of aortic flow to the beginning of mitral inflow from an apical five-chamber view [17]. Pulmonary venous flow [17,18] was recorded from the apical four-chamber view placing a 3-4 mm sample volume 1 cm into the right upper pulmonary vein. Peak S velocity (cm/s), peak D velocity (cm/s), S/D ratio, peak R velocity (cm/s) and R wave duration (ms) were measured. Colour M-mode Doppler echocardiography was performed from the apical four-chamber view with the M-mode cursor aligned parallel with LV inflow. Colour-scale was set as 55-60 cm/s and baseline shift was adjusted (40 cm/s range). Flow propagation velocity (Vp) was measured as previously described. [19]. Tissue Doppler imaging (TDI) [19] was performed from the apical four-chamber view with a 8-9 mm sample volume placed at the lateral aspect of the mitral annulus. Peak velocity in relation to early filling (Em) was measured.

Tei index was assessed from Doppler recordings of LV inflow and outflow. From mitral inflow, the time interval from cessation to onset of mitral inflow was measured (A-interval). Ejection time (B-interval) was measured from LV outflow velocity curve recorded from an apical long-axis view. Tei index was calculated as (A–B)/B [12].

2.2.3. Definition of LV-dysfunction (LVD)
SHF was defined as an EF ≤45% irrespective of LV filling pattern. HFPSF was considered when EF was greater than >45% in combination with an abnormal filling pattern (stages 1-3). The filling pattern was categorized as normal, impaired relaxation (stage 1), pseudo normal (stage 2) or restrictive (stage 3) (Appendix A). Grading of an abnormal filling pattern was based on previous guidelines [17-20] and definitions were prespecified.

2.2.4. Reproducibility of echocardiography
Variability was expressed as the mean percent error, derived as the absolute difference between two sets of observations divided by the mean of the observations. Based on two different examiners, the inter-observer variability was as follows: EF 9±4%, Tei index 6±3%, E/A ratio 8±9%, DT 8±5%, IVRT 7±5%, S/D ratio 10±7%, Rdur–Adur 18±4%, E/EVp 11±8%, E/Em 7±6%.

2.3. Neurohormone analyses
Venous blood samples for hormone analyses were taken in the morning after an overnight fast and after 30 min of rest in supine position. Blood was drawn into prechilled EDTA tubes except for the catecholamine sample. Plasma was immediately separated at 4 °C by centrifugation and was immediately frozen and stored at –80 °C. All medicine was paused in the morning on the examination day.

p-NT-proBNP concentration was measured with a fully automated (Elecsys 2010 analyzer) non-competitive electrochemiluminescence immunoassay (Roche Diagnostics). Detection limit was 5 pg/ml. Intra-assay coefficient of variation (CV) was 3% for low- and 2.9% for high-concentration patient samples.

P-renin activity was determined by an antibody trapping method [21]. Detection limit was 0.15 mIU/l. Intra- and inter-assay CV were 6.8% and 5.3%, respectively.

Angiotensin II immunoreactivity in plasma was detected with a specific antibody (ab-5-030682). Detection limit was 1.4 pg/ml. Extraction recovery of unlabeled angiotensin II was 100%. Intra- and inter-assay CV were 6.4% and 6.5%, respectively.

P-Aldosterone concentration was determined with a competitive radioimmunoassay (Coat-A-Count®, Diagnostic Products). Detection limit was 11 pg/ml. Intra- and inter-assay CV were 2.9% and 10.3%, respectively.

P-noradrenaline concentration was determined with a competitive ELISA kit (DLD Diagnostika). Blood was immediately transferred to a chilled polyethylene tube with pH 6-7. Detection limit was 40 pg/ml. Intra- and inter-assay CV were 10.4% and 14.5%, respectively.

2.4. Patient management
In SHF, an ACE-inhibitor or an angiotensin II receptor blocker was prescribed. Subsequently, a β-blocker was introduced and titrated to target dose. Spironolactone (25 mg) was reserved for SHF patients in NYHA class III. Patients with clinical signs of fluid retention received diuretics.

In patients with hypertension and HFPSF, an ACE-inhibitor was first choice. If adequate blood pressure lowering was not achieved treatment with a thiazide or calcium antagonist was instituted.

Patients with ischaemic heart disease and HFPSF received a β-blocker. In case of β-blocker intolerance or need of supplemental treatment, calcium antagonists or nitrates were given. Coronary angiography was performed in patients with inducible ischaemia on exercise testing or directly, and patients were subsequently revascularised when appropriate. However, older patients free of angina pectoris on monotherapy did not undergo further evaluation.

2.5. Functional class
Functional status was graded by assessment of New York Heart Association (NYHA) functional class [22]. Supplemental criteria were used to categorize patients in each NYHA class [23]. NYHA class was assessed prior to echocardiography and blinded to NT-proBNP.

2.6. Quality of life
QOL was estimated from The "Minnesota-Living with Heart Failure Questionnaire" (MLHFQ) comprising 21 questions [24]. The score of each question was graded from 0 to 5 and increased with severity. Maximum score was 105 points. The questionnaire was filled in at home.

2.7. Statistics
Neurohormonal data approximated a normal distribution after logarithmic (natural logarithm) transformation. Continuous data are expressed as medians and 10th and 90th percentiles. The null hypothesis of equal population medians was tested with Kruskal-Wallis test. If rejected, two-sample comparisons were performed using Wilcoxon rank-sum test. Frequencies were compared with a two-sided Fisher's exact test. Bivariate correlations were assessed using nonparametric Spearman correlation coefficient. Friedsman's test was used to test differences in repeated measurements. Potential predictors of an unchanged or increased NYHA class were tested by logistic regression and potential predictors of QOL at 1 year were tested by linear regression. For both models, univariate regressions of selected parameters were followed by multivariate regression with forced entry of four-five preselected clinical parameters. The added prognostic value of NT-proBNP and Tei index in relation to the clinical model were then tested by stepwise addition of covariates. A significance level of 5% was used. STATA 8.0 (Stata Corporation, TX, USA) was used for statistical analyses.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Conclusion
 References
 
3.1. Patient characteristics
Abnormalities in filling pattern were found in 80 patients. In 58 of these patients, systolic function was preserved and in the remaining 22 SHF was present. Baseline characteristics according to these groups are summarised in Table 1. Patients with SHF frequently had a history of ischaemic heart disease (55%) compared to patients with HFPSF who more frequently had a history of hypertension (69%). Median NT-proBNP concentrations were higher in patients with LVD (2285 pg/ml (595; 6395) in patients with SHF and 199 pg/ml (92; 500) in patients with HFPSF) compared to patients without LVD (55 pg/ml (24; 122), p=0.0001). In contrast, no differences in renin, angiotensin II or noradrenaline concentrations were found. Tei index was increased in patients with LVD and was closely correlated with NT-proBNP (r=0.75, p=0.0001) (Fig. 1).


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  		Table 1 Baseline characteristics of study subjects based on the diagnostic group

 


Figure 1
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  		Fig. 1 Scatter plot demonstrating the relation between baseline p-NT-proBNP level (pg/ml) and Tei index (r=0.75, p=0.0001).

 
The functional limitation was mild in patients with HF; 55 (69%) patients were in NYHA class II, 24 (30%) in NYHA class III and 1 patient (1%) was in NYHA class IV (Table 1). NYHA class was significantly higher in patients with SHF compared with HFPSF; in addition, NYHA class was significantly correlated with NT-proBNP (r=0.61, p=0.0001) and with Tei index (r=0.54, p=0.0001). Also QOL was higher in patients with LVSD (p=0.03, Table 1) and QOL demonstrated a weak correlation with p-NT-proBNP (r=0.28, p=0.02) and NYHA-class (r=0.36, p=0.001).

3.2. Follow-up
Complete follow-up data were available in 78 HF-patients since 2 patients died of non-cardiac reasons; in addition, QOL was not available in 7 patients.

All patients with SHF received either an ACE-inhibitor or an angiotensin II receptor blocker; in addition, most were treated with a β-blocker (81%) and 65% were treated with diuretics. Spironolactone was given to 71% of patients with SHF, reflecting the number of patients in NYHA class III. Of patients with HFPSF, 75% of patients received either an ACE inhibitor or an angiotensin II blocker and 25% received diuretics. A β-blocker or a calcium antagonist was used in 33%. Of the patients with HFPSF and ischaemic heart disease, nine patients (47%) underwent coronary revascularisation. During follow up, four patients with SHF had 9 hospitalisations, while only one patient with HFPSF was hospitalised for HF. Patients with SHF had 5.6 unscheduled ambulatory visits per patient and patients with HFPSF had 2.8 visits.

During follow up NT-proBNP fell in patients with SHF and HFPSF (p=0.0001 and 0.02, respectively, Fig. 2a). Compared to baseline QOL (Table 1), QOL was improved at 12 months so that patients with SHF had a median QOL of 18 (5; 69, p=0.01) and patients with HFPSF had a median QOL of 16 (4; 46, p=0.02). NYHA functional class was also improved in both groups of LVD (p=0.002 and p=0.05, respectively). Thus, at 12 months, 3 patients were in NYHA class I, 11 patients were in NYHA class II, and 7 patients were in NYHA class III among patients with SHF. Among patients with HFPSF, 13 patients were in NYHA class I, 42 patients were in NYHA class II, and 2 patients were in NYHA class III. The change in NT-proBNP and change in NYHA class correlated poorly (r=0.19, p=0.02).


Figure 2
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  		Fig. 2 Box plots demonstrating (a) p-NT-proBNP levels (pg/ml) and (b) Tei index at each scheduled visit 0, 3, 6 and 12 months after inclusion, divided according to the degree of LVD. The Y-axis is on a log scale. The box indicates the lower and upper quartiles and the central line is the median. The points at the end of the whiskers are the 5% and 95% values. SHF=systolic heart failure. HFPSF=heart failure with preserved systolic function.

 
Close to 50% of patients with SHF and 35% with HFPSF demonstrated improved diastolic function after 12 months. Despite this, global LV function assessed by Tei index did not change significantly after 12 months (Fig. 2b). However, the change in Tei index (delta Tei) over 12 months correlated with the change in NT-proBNP (delta log NT-proBNP) (r=0.36, p=0.001). The correlation was most powerful in patients with SHF (r=0.61, p=0.005).

During follow-up, NYHA class improved in 31 patients and was unchanged or increased in the remaining 47 patients (Fig. 3). Tei index increased in patients where no improvement in NYHA class was seen (median –0.02 (–0.16; 0.09)), while Tei index in patients with functional improvement was reduced (median 0.06 (–0.19; 0.35), p=0.02). Although NT-proBNP concentrations fell in most patients with LVD the reduction was significantly greater in patients with improvement in NYHA class compared with no improvement (median 384 pg/ml (–173; 5885) vs. median 64 pg/ml (–107; 360), p=0.002). Thus, the fraction of patients with a reduction in p-NT-proBNP of at least 30% was significantly higher in the group with improvement in NYHA class compared to the group with no improvement (75% versus 45%, p<0.01).


Figure 3
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  		Fig. 3 Scatter plots demonstrating the relationship between delta NT-proBNP (pg/ml) and delta Tei index over 12 months, divided according to achievement of functional improvement (n=31) or resistance to functional improvement (n=47). The changes in NT-proBNP and Tei-index were significantly different in relation to the functional group (p=0.002 and p=0.02, respectively).

 
3.3. Predictors of no functional improvement after 12 months
On univariate logistic regression, resistance to improvement in NYHA class was associated with preserved LV function, low baseline NT-proBNP and high BMI (Table 2). In a multivariate logistic regression model with clinical data (age, sex, BMI and FEV1/FVC), NT-proBNP remained an independent predictor (Table 3). Tei index was also an independent predictor (p=0.003) of no improvement in NYHA class in a multivariate logistic regression model with clinical data (age, sex, BMI and FEV1/FVC) plus Tei index. The incremental value of NT-proBNP and Tei index were assessed in a stepwise model. Addition of NT-proBNP to a model of clinical variables increased the overall log likelihood ratio chi-square from 9.32 to 20.18; (p=0.001). Almost identical incremental value was obtained by addition of Tei index (increase in log likelihood chi-square to 20.67 (p=0.001). However, no additional information was gained by inclusion of both, p=0.12 (Fig. 4).


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  		Table 2 Univariate predictors of resistance to improvement in NYHA functional class and QOL after 12 months of follow-up

 


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  		Table 3 Multivariate regression model for resistance to improvement in NYHA functional class after 12 months of follow-up

 


Figure 4
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  		Fig. 4 Chi-square values for logistic regression models including first clinical variables and then stepwise addition of p-NT-proBNP or Tei index or addition of both variables. Increments of {chi}(1)2≥3.84 indicate that the variable added to the model is significant (p<0.05).

 
3.4. Predictors of resistance to improvement in QOL after 12 months
On univariate linear regression, no improvement in QOL was also associated with preserved LV function, and low concentrations of baseline NT-proBNP and p-noradrenaline (Table 2). In a multivariate linear regression model including clinical baseline parameters (age, sex, BMI, FEV1/FVC and baseline NYHA class), the goodness-of-fit was relatively poor. The total variation (R2) explained by the model was 17.2%. By univariate linear regression of NT-proBNP, R2 was 16.7%. Adding NT-proBNP to the clinical model did not increase the variability explained by the model (R2=16.45). Adding Tei index to the clinical model had no incremental value (R2=16.2%).


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Conclusion
 References
 
4.1. Natriuretic peptides
B-type natriuretic peptide is a cardiac neurohormone secreted from the myocytes in response to myocardial stretch [25,26] and ischaemia [27]. BNP is increased in patients with systolic as well as diastolic dysfunction, where it correlates to functional class and prognosis [28,29]. BNP possess natriuretic properties and expression of BNP may in the early phase of HF suppress activation of RAAS [1,25,26,28,30]. This is consistent with the present study where plasma neurohormonal activation was restricted to NT-proBNP whereas no RAAS hyperactivity could be identified.

Few studies have described serial changes in cardiac peptides in untreated patients with newly diagnosed HF. We found that NT-proBNP concentrations were reduced after institution of treatment and that less reduction was seen in patients with no symptomatic improvement. However, the overall change in NT-proBNP correlated poorly with change in NYHA class. This is in accordance with a previous study, where Lee et al. [7] demonstrated a strong association between baseline NYHA score and BNP, while the changes in BNP and NYHA class correlated poorly. In addition Jourdain et al. [6] found that although BNP increases with increasing NYHA class, a wide range of BNP levels were present within each NYHA class, and objective assessment of functional status by exercise testing demonstrated lowest BNP levels among the patients with a high physical performance.

Although we found a reduction in NT-proBNP and QOL in the majority of patients, baseline NT-proBNP and QOL were higher and were more markedly reduced during follow-up in the group with SHF. A lower QOL in patients with HFPSF was as expected associated with better NYHA functional class, and is in accordance with previous findings [31]. Hobbs et al. [32] also demonstrated a considerable potential of improvement in QOL among patients with SHF if they were rendered asymptomatic on appropriate treatment. In the present study, poor baseline LV-function and high NT-proBNP level indicated a potential for improvement in QOL and functional class, while patients with only mild LVD did not have that potential. One might speculate that this finding is in accordance with the demonstrated lower mortality rate among the most neurohormonally activated patients (high concentrations of atrial natriuretic peptide, noradrenaline and RAAS hyperactivity) prior to initiation of ACE-inhibitor treatment [33,34]. However, if BNP remains high following optimization of treatment, morbidity and mortality rates are increased [8,9,35,36]. A decrease in BNP is associated with better outcome [9,35]. Bettencourt et al. [35] stratified hospitalised patients with decompensated HF according to the change in p-BNP during hospitalisation and demonstrated a significantly lower event rate in patients with at least a 30% reduction. Accepting this degree of reduction as a relevant measure, we were able to demonstrate that the fraction of patients with at least a 30% reduction in p-NT-proBNP during follow up was significantly higher in patients with functional improvement. However, it is difficult to assess the clinically significant level of improvement in BNP for the individual patient.

4.2. Tei index
The Doppler echocardiographic Tei index combines time intervals of contraction and relaxation in an overall index of LV function. In normal subjects, the index has a narrow range and seems to increase progressively as deterioration in LV function evolves [12,13]. This also seems to be the case when LV systolic function appears preserved. Tei index has previously been shown to possess considerable prognostic information in patients with dilated and restrictive cardiomyopathies and in patients with acute myocardial infarction [14,15,37]. No previous studies have assessed Tei index in incident cases of HF with predominantly preserved systolic function. We have demonstrated in patients with suspected HF, that Tei index effectively separates patients with no abnormalities on echocardiography, from those with even mildly depressed function, and correlates well with NT-proBNP. Ono et al. [38] also demonstrated a fair correlation between Tei index and BNP in 74 patients with various heart diseases with little functional impairment (81% were in NYHA class I). It seems that the factors that trigger release of natriuretic peptides also affect the Tei index. This also seems to be the case during follow-up, where we also found changes in Tei index to correlate with changes in NT-proBNP. This correlation was best for patients with high baseline concentrations of NT-proBNP and increased Tei index, i.e. patients with the greatest potential for improvement. In contrast to NT-proBNP where some degree of decrease was seen in most patients, there was an increase in Tei index in patients where no functional improvement was seen during follow-up.

4.3. Study limitations and clinical implications
The proportion of patients with HFPSF was high in the present study but the finding is in accordance the results of the Doppler echocardiographic Rochester cross-sectional survey of more than 2000 randomly selected residents in Olmsted County [5]. Although our data are in accordance with this, the in- and exclusion criteria (especially medical treatment) in the present study may have increased the number of patients with non-systolic HF. Also the high prevalence of patients with hypertension may have increased the proportion of patients with HFPSF.

The results of the present study are influenced by the large number of patients with mild LVD. The sample size and the presence of predominantly mild LVD limit the prognostic power of the multivariate models and preclude more variables to be included in analyses. The study demonstrates that patients with the mildest forms of LVD only had a limited potential for functional improvement in relation to therapeutic intervention, based on NYHA score and improvement in QOL. Increasing BMI was a univariate predictor of no functional improvement and BMI tended to be higher among patients with HFPSF compared to patients with SHF, which is a general finding [2]. In the present study, it seems likely that dyspnoea in some patients with grade 1 diastolic dysfunction was due to other non-cardiac causes, especially obesity. This may partly explain the modest correlation between changes in NYHA and delta NT-proBNP in patients with HFPSF. Further, patients with HFPSF were predominantly in NYHA class II at the time of diagnosis. A more objective and nuanced assessment of functional status by exercise testing could possibly have provided a more differentiated distribution of patients which might have made the models more informative and might have improved the correlation between functional score and NT-proBNP/Tei index.

The limited information in the regression model of QOL was unexpected. The limited information is probably related to the predominance of mild HF with little or no potential for improvement in relation to therapeutic intervention and is also likely an indication of the subjectivity of the score, as it depends mainly upon the patients' perception and description of health problems, which might be influenced by non-cardiac conditions. It has also been argued that MLHFQ does not distinguish well between different severities of HF [39].

Even though it could seem that the factors that trigger release of natriuretic peptides also affect the Tei index, and even though multivariable analysis indicates Tei index and NT-proBNP to be of equal value in identifying patients with no functional improvement, it could seem that changes in Tei index may be easier to interpret in the clinical setting than NT-proBNP, where medical treatment per se modulates p-NT-proBNP. Thus, no change or an increase in Tei index after institution of therapy seems to warrant closer follow-up and possibly more aggressive therapeutic interventions. Future studies with greater power and extended follow-up should evaluate if assessment of serial changes in Tei index or NT-proBNP are useful tools for the detection of patients with lack of functional improvement because of progressive LVD. Future studies should also assess whether aggressive therapeutic interventions in this group of patients with predominantly HFPSF can prevent progression to predominantly SHF.

The present study demonstrates an association between symptomatic HF, neurohormonal activation and abnormal Doppler echocardiographic diastolic filling pattern. As we did not obtain invasive pressure-volume relationship data, we cannot assess whether an underlying intrinsic diastolic myocardial disorder was present. The study was prospective. To which degree the changes in indices over time reflect the longitudinal follow-up and to which degree it was an effect of therapeutic intervention, is uncertain.


   5. Conclusion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
References
 
The present study demonstrates that in patients with newly diagnosed HF, NT-proBNP correlates well with overall LV function assessed by the Doppler echocardiographic Tei index before institution of therapy. Both NT-proBNP and Tei index were predictors of functional class at 12 months; however, no additional prognostic information was gained from a combination. Patients characterized by advanced LVD and neurohormonal activation demonstrated a potential for functional improvement and for improving QOL, while prediction of functional status based on NYHA score was of little value in a population with predominantly HFPSF because of a limited change in this group.

Evaluation of serial changes in NT-proBNP or Tei index seemed to be of value in patients with lack of functional improvement, but it could seem that serial changes in Tei index may be easier to interpret in the clinical setting than changes in NT-proBNP.


   Acknowledgements
 
This work was supported by a grant from The Danish Heart Foundation. We thank Professor Werner Vach for statistical support.


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

  1. Schrier R.W., Abraham W.T. Hormones and hemodynamics in heart failure. N Engl J Med (1999) 341:577–585.[Free Full Text]
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J. N. Kirkpatrick, M. A. Vannan, J. Narula, and R. M. Lang
Echocardiography in Heart Failure: Applications, Utility, and New Horizons
J. Am. Coll. Cardiol., July 31, 2007; 50(5): 381 - 396.
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