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European Journal of Heart Failure 2004 6(6):735-743; doi:10.1016/j.ejheart.2003.11.013
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© 2004 European Society of Cardiology

Restrictive filling pattern is associated with increased humoral activation and impaired exercise capacity in dilated cardiomyopathy

Alexander P. Patrianakos, Frangiskos I. Parthenakis, Evangelos A. Papadimitriou, George F. Diakakis, Panagiotis G. Tzerakis, Dragana Nikitovic and Panos E. Vardas*

Cardiology Department, University Hospital of Heraklion P.O. Box 1352 Stavrakia, Heraklion Crete, Greece

* Corresponding author. Tel.: +30-2810-392632; fax: +30-2810-542055. E-mail address: cardio{at}med.uoc.gr


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
Objectives: Although heart failure (HF) is characterized by increased proinflammatory cytokines, natriuretic peptide levels and impaired exercise capacity, the effect of concomitant diastolic dysfunction on those parameters has not been adequately studied.

Methods: We analyzed circulating levels of IL-1, IL-6, TNF-{alpha} and its soluble receptors, sTNFRI and sTNFRII, Nt-ANP and Nt-BNP natriuretic peptides in 81 patients, aged 56±12 years, with non-ischemic dilated cardiomyopathy (NIDC), LVEF 29.7±7.75% and functional NYHA class II-III. An echocardiographic study and cardiopulmonary exercise test (CPE) were performed in all patients.

Results: Patients were divided into restrictive (24 patients, group I) and non-restrictive (57 patients, group II) groups, according to their transmitral-filling pattern. No differences in LV dimensions or LVEF were found between the two groups. Group I showed increased levels of IL-6 (P=0.006), TNF-{alpha} (P=0.05), sTNFRII (P=0.02), Nt-ANP (P<0.001) and Nt-BNP (P<0.001) and decreased exercise duration (P<0.001) and PVO2 (P<0.001) compared to group II. The strongest independent predictors for restrictive filling pattern were Nt-ANP and IL-6 levels, while Nt-BNP levels were the strongest PVO2 predictor.

Conclusions: Restrictive filling pattern implying greater diastolic dysfunction may contribute to increased cytokine production in the heart failure syndrome, as well as greater increases in natriuretic peptides and decreased exercise tolerance.

Key Words: Abbreviations • NIDC, non-ischemic dilated cardiomyopathy • HF, heart failure • LV, left ventricle • EF, ejection fraction • RFP, restrictive filling pattern • IL-1, interleukin-1beta • IL-6, interleukin-6 • TNF-{alpha}, tumor necrosis factor-alpha • Nt-ANP, N-terminal pro-atrial natriuretic peptide • Nt-BNP, N-terminal pro-brain natriuretic peptide • CPE, cardiopulmonary exercise test • PVO2, maximal oxygen consumption at peak exercise

Received March 26, 2003; Revised October 23, 2003; Accepted November 30, 2003


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
Proinflammatory cytokines such as Interleukin-1 (IL-1), Interleukin-6 (IL-6) and Tumor Necrosis Factor-alpha (TNF-{alpha}) have been recently identified as contributors to the syndrome of chronic HF [1] and it has become abundantly clear that the elaboration of these biologically active molecules is also observed in direct relation to New York Heart Association (NYHA) functional class [2,3]. Moreover, previous studies have suggested that elevated levels of cytokines and cytokine receptors predict a worse clinical outcome in those patients [2,4].

In the setting of HF, natriuretic peptides such as atrial and brain natriuretic peptides are also increased and elevated levels of these substances identify those at greatest risk of future serious cardiovascular events [5–8]. Plasma levels of brain natriuretic peptide (BNP), measured upon initial presentation, provide prognostic information in patients with chronic HF as well as in those with asymptomatic or minimally symptomatic left ventricular (LV) dysfunction [8].

LV diastolic dysfunction, a common finding in patients with systolic dysfunction and the Restrictive Filling Pattern (RFP) as assessed by Doppler echocardiography, appears to be associated with increased mortality rate or the need for cardiac transplantation [9,10].

Although exercise tolerance, as defined by parameters of cardiopulmonary exercise (CPE), provides the most objective assessment of functional capacity in patients with HF and may be one of the best indices when to perform cardiac transplantation in eligible patients [11], there is a limited relation between PVO2 and other parameters of disease severity such as NYHA functional class, LV ejection fraction (EF) or cardiac index [12]. However, indices of LV diastolic function that may be associated with CPE capacity have been reported.

We hypothesized that advanced diastolic dysfunction as assessed by echocardiography would be associated with increased proinflammatory cytokine and natriuretic peptide levels and reduced functional capacity in patients with mild to moderate HF. Accordingly, the aim of our study was to characterize LV diastolic filling pattern in patients with HF and to measure cytokines, natriuretic peptides and functional capacity in a group of subjects with NIDC and mild to moderate HF.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Conclusions
 References
 
2.1. Study group
The study population consisted of 81 consecutive patients enrolled from the heart failure clinic of our hospital, aged <75 yrs of which 27 were women. The patients had an echocardiographic diagnosis of dilated cardiomyopathy defined as LV end-diastolic dimensions >55 mm with LVEF <45%, chronic mild to moderate HF (NYHA functional class II to III) and a clinical history >6 months. All patients were in sinus rhythm and underwent cardiac catheterization before their inclusion in the study.

Exclusion criteria were the presence of significant coronary artery disease (lumen stenosis >50% of any coronary artery, or prior myocardial infarction), severe cardiac valve disease, atrial fibrillation during the last month, long-standing diabetes mellitus (>1 year) or arterial hypertension (>180/90 mmHg, more than 1 year), chronic liver or renal insufficiency (creatinine plasma levels >1.5 mg/dl), chronic obstructive pulmonary disease, or any indication of recent infection (during last month previous to study).

All patients were in a stable condition for at least 4 weeks, with the medication individually optimized without modification in the last month before assessment of the variables outlined below. They were primarily under treatment with ACE-inhibitors (85%), diuretics (80.2%), digoxin (64.1%) and b-blockers (53%).

Fifteen healthy persons, aged 53±9.8 years, 6 women, without any history of cardiovascular disease served as the control group. The study conformed to the principles outlined in the declaration of Helsinki [13] and was approved by the Institutional Ethics Committee. All patients gave written, informed consent.

2.2. Echocardiography study
M-mode, two-dimensional and Doppler echocardiography were performed in all patients with a Hewlett-Packard Sonos 2500 echocardiographic device (Andover, Mass) and a 2.5 or 2.0 MHz wide-angle phased-array transducer and all examinations were recorded on videotape.

M-mode echocardiographic recordings were obtained from the left parasternal window and all measurements were made according to the recommendations of the American Society of Echocardiography [14].

LV volumes were measured from the apical 4-chamber view of the two-dimensional echocardiogram with a modified Simpson's rule algorithm. Data were analyzed as the mean of three cardiac cycles. Two independent investigators calculated LVEF. In the case of a disagreement (>7%), a third investigator reviewed the findings and a majority decision was reached.

Spectral Doppler recordings from the mitral inflow were obtained from the apical 4-chamber view to assess LV filling dynamics. The pulsed-wave Doppler sample volume was positioned between the tips of the mitral leaflets to derive the following variables: (1) peak early (E wave) and late (A wave) transmitral filling velocities in centimeters per second; (2) E/A ratio; and (3) deceleration time of the E (DTE) velocity in milliseconds (from peak E velocity to baseline).

The Valsalva manoeuvre with simultaneous recording of mitral inflow PW-Doppler was performed on patients who showed a ‘normal’ filling pattern.

Cardiac output (CO) was calculated using PW-Doppler from 5-chamber apical view and two-dimensional-echo data of the LV outflow tract derived from long parasternal axis according to the formula: CO={pi}x(d/2)2xVTILVOTxHR where d=diameter of LVOT derived from the two-dimensional-longitudinal parasternal axis, VTILVOT=pulsed wave Doppler flow velocity time integral through the LVOT and HR=Heart rate.

Color Doppler flow mapping was used to grade mitral regurgitation on a scale of 0+ to 4+ where 0+ indicated no obvious mitral valve regurgitation and 4+ indicated severe mitral valve regurgitation [15].

The patients were divided into non-restrictive (with delayed or pseudonormal relaxation) and restrictive filling pattern groups on the basis of the E/A ratio, E-wave deceleration time and the response of transmitral filling pattern to the strain phase of Valsalva maneuver. Delayed relaxation pattern was defined by E/A ratio <1 and DTE>220 ms, pseudonormal pattern by E/A ratio between 1 and 2 with DTE >140 ms and reverse to delayed relaxation during the strain phase of Valsalva maneuver [16] while a restrictive filing pattern was defined either by E/A ratio >2 or E/A ratio between 1 and 2 with DTE<140 ms [17].

2.3. Cardiopulmonary exercise testing
All patients underwent an exercise test (mean time ±5 days after echocardiography study and blood sampling) using a Marquette treadmill device (Max-1), typically during the morning and after at least 3 h without food, coffee or cigarettes. A graded, symptom-limited test was performed using a Naughton protocol. A 12-lead ECG was monitored continuously, with recordings every 2 min at the end of each stage.

Gas exchange data were collected continuously with an automated breath-by-breath system (Oxycon A, version 3.1, Jaeger).

The exercise duration was defined as the time from the start of exercise until its cessation because of dyspnea or fatigue. Maximal oxygen consumption at peak exercise (PVO2) was calculated as the average oxygen consumption value over the final 30 s of exercise.

2.4. Humoral variables
Fasting blood samples were collected from an antecubital vein after a 20-min supine rest into pyrogen-free vacuum blood collection tubes (Greiner labortehnik, Kremsmunster, Austria) with EDTA as anticoagulant. Tubes were centrifuged within 2 h of collection at 3000 rev./min and 4 °C for 15 min to obtain plasma or serum, which was then separated in multiple aliquots and stored at –70 °C before assay.

2.4.1. Enzyme immunoassays (ELISA)
Concentrations of trimeric, plasma bioactive TNF-{alpha} (detection limit 0.18 pg/ml), plasma IL-6 (detection limit 0.1 pg/ml) and serum IL-1 (detection limit 0.1 pg/ml) were determined by a high sensitivity enzyme linked immunoassay, according to the manufacturer's instructions (R and D Systems, Abingdon, UK). Plasma concentrations of soluble TNF-{alpha} receptors sTNFRI, (detection limit 3.0 pg/ml) and sTNFRII (detection limit 1.0 pg/ml), were measured by assays employing the sandwich enzyme immunoassay technique as instructed by the manufacturer (R and D Systems, Abington, UK).

Plasma levels of N-terminal-proAtrial (Nt-ANP) (detection limit 50 fmol/ml) and N-terminal-pro-brain natriuretic peptides (Nt-BNP) (detection limit 5 fmol/ml) were measured by ELISA according to the manufacturer's instructions (Biomedica, Wien, Austria). We measured the Nt-BNP levels because both NT pro brain and brain natriuretic peptide levels have been shown to accurately reflect heart failure severity and seem to provide much the same information [18]; hence, these blood tests have inherent, objective contributions to patient assessment [19] but the half-life of Nt-BNP is 120 min, while the half-life of brain natriuretic peptide is 22 min [20], suggesting that NT-BNP can be used faithfully in the evaluation of clinical stable patients.

Intra-and inter-assay coefficients of variation for all enzyme immunoassays were <5% and <10%, respectively.

2.5. Statistical analysis
Summary data are expressed as mean±S.D. Correlations between continuous variables were assessed using the Pearson correlation coefficient. For ordinal data the Spearman rank correlation was used. Stepwise linear regression analysis was used to assess which of the statistically significant correlations between variables were independently correlated with exercise duration and PVO2. Binary logistic regression analysis was used when the dependent variable was dichotomous (entry 5%, removal 10%).

Receiver operator characteristic (ROC) curves were analyzed to evaluate the sensitivity vs. 1-specificity of cytokines and natriuretic peptides at different diagnostic thresholds in predicting the restrictive LV filing pattern. The area under the curve was reported.

Group comparisons were made using the unpaired Student's t-test or the Mann–Whitney U test, as appropriate. A two-tailed significance level of 0.05 was considered statistically significant. All analyses were performed using a commercially available statistical package (SPSS for Windows 11.0).


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Conclusions
 References
 
3.1. Patient characteristics
Patient characteristics are summarized in Table 1. Patients with NYHA III functional class evidenced more increased levels of IL-1 (0.87±0.51 vs. 1.2±0.69 pg/ml, P=0.01), IL-6 (3.5±2.3 vs. 5.7±4.1 pg/ml, P=0.02), TNF-{alpha} (2.5±1 vs. 3.0±0.89 pg/ml, P=0.03), sTNFRI (1.41±0.37 vs. 1.71±0.51 ng/ml, P=0.01), Nt-ANP (2.8±1.4 vs. 4.7±2.8 pmol/ml, P<0.001) and Nt-BNP (0.6±0.19 vs. 0.95±0.50 pmol/ml, P<0.001) levels compared to those in NYHA II class. Binary regression analysis showed that Nt-BNP levels were the most powerful independent predictor of NYHA functional class (r=0.46, P<0.001) among all measurement humoral parameters (Nt-BNP, Nt-ANP, IL-1,IL-6,TNF-{alpha},sTNFRI, sTNFRII), followed by IL-6 (r=0.51, P=0.02).


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  		Table 1 Patient's functional, clinical, and echocardiographic characteristics

 
According to transmitral LV filling pattern 24 patients were classified as restrictive (group I) and 57 patients as non-restrictive (group II) group.

There were no significant differences in medical treatment used for the two groups apart from diuretics which were used more frequently in group I patients (0.98% vs. 0.69%, respectively, P<0.01).

There were no significant differences in LV diastolic or systolic diameters or LVEF between the two groups or the presence of mitral regurgitation (2.12±0.79 vs. 1.78±0.7, P=0.08).

Group I patients had higher NYHA class (2.5±0.51 vs. 2.2±0.4, P=0.02), increased Left Atrial (LA) diameter (P=0.01) and impaired Cardiac Output (CO) (P=0.001) compared to group II.

When we analyzed the natriuretic peptide and cytokines levels according to NYHA class in either subgroup we found that in the non-restrictive group NYHA class III patients had increased levels of Nt-ANP (2.8±1.4 vs. 2.1±0.9 pmol/ml, P=0.03) and IL-6 (4.8±2.8 vs. 3.1±1.8 pg/ml, P=0.01) compared to NYHA class II patients, but the effect of NYHA class on cytokine levels disappears in the restrictive group, where NYHA class III patients only showed increased levels of Nt-ANP (6.6±3.1 vs. 4.3±2.1 pmol/ml, P=0.04).

3.2. Relation of LV diastolic filling pattern and humoral activation
The circulating plasma levels of cytokine and natriuretic peptide levels were significantly elevated in patients compared to controls (all P<0.001, Table 2).


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  		Table 2 Cytokines and Natriuretic peptides levels in patients with NIDC and controls

 
Group I patients showed increased levels of IL-6 (P=0.006), TNF-{alpha} (P=0.05) and sTNFRII levels (P=0.02) as well as Nt-ANP (P<0.001) and Nt-BNP (P<0.001) compared to group II patients (Fig. 1).


Figure 1
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  		Fig. 1 Mean cytokine (A) and natriuretic peptides (B, C) circulating levels in patients with Non-ischemic dilated cardiomyopathy (NIDC) according to LV diastolic filling pattern. Non-Rest.=Patients group with non-restrictive filling pattern, Restr.=Patients group with restrictive filling pattern.

 
Sixteen patients belonging to group II who had pseudonormal filling pattern, showed reduced values of IL-6 (3.1±1.9 vs. 5.7±4.7 pg/ml, P=0.04), Nt-ANP (2.3±1.0 vs. 5.4±2.8 pmol/ml, P<0.001) and Nt-BNP (0.5±0.2 vs. 0.8±0.3 pmol/ml, P=0.005) and a trend of reduced TNF-{alpha} (2.4±0.6 vs. 3.0±1.1 pg/ml, P=0.08), sTNFRI (1.3±0.2 vs. 1.6±0.4 ng/ml, P=0.07) and sTNFRII (2.3±0.6 vs. 2.8±0.9 ng/ml, P=0.06) levels, compared to group I patients.

Binary logistic regression analysis showed that among cytokines (TNF-{alpha}, sTNFRII, IL-6) the IL-6 level (95% CI 1.04–1.41, P<0.001) was the strongest independent variable for predicting RFP. However, when we analyzed all cytokines and natriuretic peptide levels together (Nt-ANP, Nt-BNP, TNF-{alpha}, sTNFRII, IL-6), we found that Nt-ANP level was the strongest independent variable (95%CI 1.63–3.9, P<0.001), followed by IL-6 levels.

ROC curve analysis showed that among cytokines sTNFRII was the most sensitive and specific parameter to predict RFP and a cut-off value of 2.15 ng/ml had 75% sensitivity and 54.6% specificity in diagnosing the presence of restrictive filling among patients with systolic dysfunction. Plasma levels of natriuretic peptides showed a similar sensitivity and specificity in predicting RFP and indicated that both sensitivity and specifity were greater in peptides than in cytokines. Cut-off points 2.75–0.62 pmol/ml for Nt-ANP and Nt-BNP had 83.3%–79.2% sensitivity and 75.4%–77.2% specificity, respectively (Fig. 2).


Figure 2
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  		Fig. 2 Receiving operating curve analysis assessing the sensitivity and specificity of cytokines (right graph) and natriuretic peptides (left graph) levels in predicting LV restrictive filling pattern in patients with NIDC.

 
3.3. Relation of exercise capacity and LV diastolic filling pattern
Group I patients exhibited impaired exercise duration (P=0.004) and PVO2 (P<0.001) compared to group II (Fig. 3).


Figure 3
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  		Fig. 3 Maximal Oxygen consumption at peak exercise (PVO2) according to LV filling pattern in patients with NIDC. Non-Restr.=Patients group with non-restrictive filling pattern, Restr.=Patients group with restrictive filling pattern.

 
Univariate analysis showed that exercise duration correlated with NYHA class (r=–0.30, P=0.006), TNF-{alpha} (r=–0.32, P=0.003), Nt-ANP (r=–0.34, P=0.001) and Nt-BNP (r=–0.43, P<0.001), while PVO2 correlated with functional NYHA class (r=–0.23, P=0.03), Nt-ANP (r=–0.44, P<0.001) and Nt-BNP levels (r=–0.55, P<0.001).

Multivariate linear regression analysis revealed that among cytokines and natriuretic peptides (Nt-BNP, Nt-ANP, IL-6, TNF-{alpha}, sTNFRII) the only strong independent variable for predicting PVO2 was the Nt-BNP level (P<0.001). According to our statistical analysis the PVO2 may be calculated from the formula: PVO2=27.81–9.80xNt-BNP (Rsq=0.31).

When we examined the relationship between PVO2 and humoral parameters in each of the two groups separately, a significant finding was that in the non-restrictive group the PVO2 showed a stronger correlation with the Nt-BNP levels (r=–0.55, P<0.001) than in the restrictive group (r=–0.41, P=0.04), while the Nt-ANP levels correlated with PVO2 in the restrictive group (r=–0.47, P=0.02) (Fig. 4).


Figure 4
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  		Fig. 4 Relationship between natriuretic peptides levels and maximal oxygen consumption (PVO2), in all patients with NIDC and in the two groups separately. (See text for details). Non-Restr.=Patients group with non-restrictive filling pattern, Restr.=Patients group with restrictive filling pattern.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Conclusions
 References
 
It has recently become apparent that in addition to neurohormones, proinflammatory cytokines are also expressed in the setting of heart failure and may contribute to disease progression by virtue of the direct toxic effects that these molecules exert on the heart and circulation. Thus, in contrast to the findings observed in non-failing hearts, TNF-{alpha} and IL-1 mRNA [21,22] appear to be persistently expressed in the failing human myocardium. However, the mechanism for persistent TNF mRNA and protein expression in the failing heart is not known.

Although proinflammatory cytokines such as TNF-{alpha} have traditionally been thought to be produced by the immune system, one of the more recent intriguing observations is that virtually all nucleated cell types within the myocardium, including cardiac myocytes themselves, are capable of synthesizing tumor necrosis factor in response to various forms of cardiac injury, including myocardial ischemia, infarction and LV pressure or volume overload [23].

Furthermore, accumulating evidence indicates that atherosclerosis is an inflammatory process involving proinflammatory cytokines whose activation has also been reported in such disparate clinical and experimental conditions as sepsis, trauma, ischemia, reversible myocardial depression, transplant rejection, myocarditis and heart failure [24]. In order, to exclude other conditions that may lead to an increase in proinflammatory cytokine activation, in this study only patients with non-ischemic cardiomyopathy, clinical history >6 months and no signs of any kind of infection were included.

4.1. Diastolic dysfunction and proinflammatory cytokines
Previous studies have shown that RFP can predict the LV filling pressures with high specificity and sensitivity in the presence of depressed LV systolic function [25]. The results of this study suggest that in patients with dilated cardiomyopathy and mild to moderate heart failure, cytokine level increase is associated with advanced diastolic dysfunction, an effect that seems unrelated to NYHA functional class in the restrictive group. This has not been adequately studied in patients with heart failure.

In our study, patients with NIDC and RFP showed significantly elevated cytokine levels of IL-6, TNF-{alpha} and its soluble receptor sTNFRII compared to patients with non-restrictive pattern, suggesting that the distending filling pressure may provoke an increased expression of these cytokines.

We did not proceed in any further analysis on patients with pseudonormal filling pattern, given that the number in this subgroup was small and the differences in cytokine levels between them and group I patients were borderline. Also, the aim of our study was mainly to examine the humoral activation differences between patients with restrictive and non-restrictive filling patterns.

Similar findings have been reported by Kappadia et al. [23], who discovered increased TNF-{alpha} levels in patients with pressure or volume overload, while the same center reported that adult mammalian myocardium elaborates biologically active TNF-{alpha}, both ex vivo and in vivo, in response to hemodynamic pressure overloading [26].

Experimentally, it has been observed in rat hearts that at a low left ventricular distending pressure there is minimal elevation of myocardial TNF-{alpha} production, whereas a high left ventricular distending pressure is associated with a robust myocardial expression of TNF-{alpha} production. A similar induction of myocardial expression of other growth factors by left ventricular distension was recently observed in an isolated rat heart model [27]. Baumgarten et al. [28] reported that in the adult mammalian heart sustained hemodynamic overloading provokes a transient increase in proinflammatory cytokine and cytokine receptor gene expression, lending even greater support to our findings.

These experimental and clinical data support our own data, providing strong evidence that elevated diastolic filling pressures induced myocardial production of cytokines or that these cytokines may exert toxic effects on the myocardium resulting in an abnormal diastolic function. In both cases a vicious circle could be activated.

An interesting observation of our study is the relationship between diastolic dysfunction and IL-6 levels. After initial reports hypothesizing that IL-6 is evidently a marker rather than a mediator of myocardial injury, an increasing number of experimental observations now suggest that IL-6 may act as a direct cardio-depressant substance [29]. Furthermore, in cultured chick ventricular myocytes IL-6 affects Ca2+ homeostasis, by acutely decreasing transient systolic peak of calcium currents while decreasing L-type Ca2+-channel currents [30].

Among cytokines, one of the most powerful predictive markers of advanced diastolic dysfunction, as shown by ROC analysis, were the sTNFR II levels. This can, in part, explain previous observations that among other cytokines and cytokine receptors, circulating levels of sTNFRII were the best independent overall predictor of mortality [31].

It is interesting to note that circulating levels of sTNFRII are thought to reflect the increased activity of TNF-{alpha}–converting enzyme [32], a membrane-bound enzyme that cleaves both TNF and TNFRII from cell surface membranes. TNF-{alpha}–converting enzyme levels have been shown to correlate with the degree of LV systolic dysfunction in patients with dilated cardiomyopathy [33].

Thus, circulating levels of sTNFRII may be a significant predictor of worsening LV systolic and diastolic function.

4.2. Diastolic dysfunction and natriuretic peptides
Atrial natriuretic peptide is primarily released from the atria in response to volume expansion, which appears to be sensed as an increase in atrial stretch. Plasma ANP levels rise early in the course of the disease and have been used as a marker for the diagnosis of asymptomatic left ventricular dysfunction [6]. In chronic and more advanced heart failure, ventricular cells can also be recruited to secrete both ANP and BNP, in response to high ventricular filling pressures [34].

The data derived from our study suggest that both Nt-ANP and Nt-BNP are excellent markers, not only of systolic dysfunction or NYHA class, but also of diastolic dysfunction and they have a higher prognostic value than any cytokine levels in predicting RFP. These findings are in agreement with previous studies showing that ANP and BNP levels also reflect diastolic dysfunction and are particularly increased in patients with RFP [35]. Additionally, McDonagh [36] proposed that BNP is an independent predictor of high LV end-diastolic pressure and more recently, Lubien et al. [37] reported that BNP can reliably detect the presence of diastolic abnormalities on echocardiography, even in patients with normal systolic function.

4.3. Relationship between exercise capacity, diastolic function and humoral activation in patients with NIDC
The present study extends our own [38] and others’ [39] previous observations that in patients with HF, the RFP is associated with reduced CPE performance, independently of the LVEF, while a relationship was also found between exercise duration and TNF-{alpha} levels. Anker et al. [40] showed a close and inverse relationship between peak leg blood flow and the plasma concentration of TNF-{alpha}, suggesting a pathophysiological role for TNF-{alpha} in reducing peak peripheral blood flow in HF and providing a possible explanation for our finding.

Regarding natriuretic peptides, Nt-BNP showed to be related with exercise duration and PVO2 in both group of patients with NIDC and seem to be to be more predictive than Nt-ANP levels in those patients. Nt-BNP and Nt-ANP are volume sensitive hormones that have attracted the interest of investigators in the setting of HF during recent years. They have been correlated with prognosis [6–9] and correlations have been sought with changes in physical activity and deterioration in functional class in these patients. Furthermore, BNP has been found to be superior to ANP in the detection of LV systolic dysfunction.

Recently, Kruger et al. [41] reported a similar finding. They showed that BNP levels were significantly correlated with the PVO2 in patients with HF. A reasonable explanation of this is that Nt-BNP correlates with LV end-diastolic pressures and in patients with HF, in contrast to healthy individuals, exercise is associated with a marked elevation in the pulmonary wedge pressure. This can exacerbate pulmonary congestion, thereby causing dyspnea and limiting exercise capacity. Patients with elevated rest LV diastolic pressures are prone to marked elevation of capillary wedge pressure during exercise and this may be the reason for the observed correlation between natriuretic peptides and exercise capacity.

4.4. Study limitations
Our study has a number of limitations. Firstly, invasive hemodynamic or additional echocardiographic parameters such as Doppler pulmonary venous curve, Color M-Mode LV inflow propagation velocity or tissue Doppler imaging, in order to obtain further useful information about LV filling pressures and to evaluate the relation between filling pressures and cytokine and natriuretic peptide levels were not carried out. However, it is well established that in patients with systolic heart failure there is a close relationship between LV filling pressures and diastolic filling pattern. Secondly, although the influence of the course of medication on humoral parameters could not be investigated as patients were on different generic regimens of ACE-Inhibitors and beta-blockers, all patients were treated according to chronic HF guidelines, and the medications administered in each group were similar. Furthermore, the use of beta-blockers did not appear to affect our study results, as no differences between the resting HR and maximal exercise HR were observed, suggesting that there was no significant difference in sympathetic blocking. Third, peripheral blood samples were analyzed and hence discrimination as to whether the predominant source of measuring cytokines was the heart or the peripheral circulation was not possible. Finally, we investigated patients with chronic HF due to nonischemic dilated cardiomyopathy and low LVEF, as the aim of our study was to assess the effect of diastolic dysfunction on humoral activation in patients with systolic heart failure. Thus, the results cannot be generalized to other patients with diastolic dysfunction and less compromised or even preserved left ventricular systolic function.


   5. Conclusions
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
References
 
In conclusion, the presence of advanced diastolic dysfunction in patients with dilated cardiomyopathy and mild to moderate HF is related to increased proinflammatory cytokine activation, natriuretic peptide levels and impaired exercise capacity. The increased LV end-diastolic pressures and stiffness may be an additional stimulus for increased neurohumoral activation and functional deterioration in these patients.


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

  1. Levine B., Kalman J., Mayer L., Fillit H.M., Packer M. Elevated circulating levels of tumor necrosis factor in severe chronic heart failure. N Engl J Med (1990) 323:236–241.[Abstract]
  2. Torre-Amione G., Kapadia S., Benedict C.R., et al. Proinflammatory cytokine levels in patients with depressed left ventricular ejection fraction: a report from the studies of left ventricular dysfunction (SOLVD). J Am Coll Cardiol (1996) 27:1201–1206.[Abstract]
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P. Lancellotti, B. Cosyns, and L. A. Pierard
Dynamic left ventricular dyssynchrony contributes to B-type natriuretic peptide release during exercise in patients with systolic heart failure
Europace, April 1, 2008; 10(4): 496 - 501.
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