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European Journal of Echocardiography 2007 8(4):265-274; doi:10.1016/j.euje.2006.06.003
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Copyright © 2006, The European Society of Cardiology

Acute changes in N-terminal pro-brain natriuretic peptide induced by dobutamine stress echocardiography

Ilias Karabinosa, Evangelia Karvounia, Nicolaos Chiotinisb, Anastasios Papadopoulosa, Phevos Simeonidisa, Orestis Tsolasb and Demosthenes Katritsisa,*

aDepartment of Cardiology, Athens Euroclinic, 9 Athanasiadou Street, Athens 11521, Greece
bCentral Laboratories, Athens Euroclinic, 9 Athanasiadou Street, Athens 11521, Greece

Received 15 March 2006; received in revised form 24 May 2006; accepted after revision 2 June 2006.

dkatritsis{at}euroclinic.gr

* Corresponding author. Tel.: +30 210 6416600/6416664; fax: +30 210 6416738.


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Aims Aim of the study was to determine the effect of dobutamine stress echocardiography (DSE)-induced ischemia on circulating levels of N-terminal fragment of B-type natriuretic peptide (NT-pro-BNP).

Methods and results One hundred and twenty-eight patients underwent DSE for the evaluation of known or suspected coronary artery disease. NT-pro-BNP levels were measured before and 1h after completion of DSE. NT-pro-BNP levels were similar before and after DSE regardless of whether patients had (123±101.8 vs. 124.2±108.3, p=NS) or did not have inducible ischemia (96.5±70.5 vs. 100.5±71.1, p=NS). Patients with inducible myocardial ischemia had no different NT-pro-BNP levels compared to patients without inducible ischemia both before (123±101.8 vs. 96.5±70pg/ml, p=0.37) and after DSE (124.2±108.3 vs. 100.5±71.1pg/ml, p=0.55). Patients with severe inducible ischemia had significantly higher NT-pro-BNP levels compared to patients with mild or moderate inducible ischemia and patients without inducible ischemia, both before (208.5±125.5 vs. 96±78.9 vs. 96.5±70pg/ml, p=0.017 and p=0.025, respectively) and after DSE (212.5±138.1 vs. 94.8±81.1 vs. 100.5±71.1pg/ml, p=0.015 and p=0.023, respectively). NT-pro-BNP levels before DSE could be independently predicted by age (p<0.0001), presence of diabetes mellitus (p=0.002), and ejection fraction (p=0.005), but not DSE inducible ischemia.

Conclusion NT-pro-BNP is not affected by DSE-induced ischemia and cannot be used in clinical practice to improve diagnostic accuracy of DSE.

Keywords: Dobutamine stress echocardiography; Brain natriuretic peptide


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
B-type natriuretic peptide (BNP) and its N-terminal fragment (NT-pro-BNP) are neurohormones synthesized and secreted by the ventricular myocardium in response to increased wall stress.1 BNP and NT-pro-BNP have been shown to be powerful diagnostic and prognostic markers in heart failure.2–4 In addition, BNP and NT-pro-BNP levels carry prognostic significance in patients with myocardial infarction,5 acute coronary syndromes6,7 and even in asymptomatic persons.8 Elevated levels of BNP are independently associated with inducible ischemia among patients with stable coronary disease, particularly among those with a history of myocardial infarction,9 and NT-pro-BNP has a close correlation to coronary disease severity.10 In a recent study, transient myocardial ischemia induced by treadmill exercise testing was associated with an immediate rise in circulating BNP levels although the magnitude of rise was proportional to the severity of ischemia, although these changes were less pronounced for NT-pro-BNP levels.11 Furthermore, exercise-induced increases in BNP and NT-pro-BNP have been reported to double the sensitivity of the exercise test for detecting ischemia without reducing specificity.12

Dobutamine stress echocardiography (DSE) has been widely used for assessment of myocardial ischemia and viability,13 but its effect on serum NT-pro-BNP levels is unknown. We hypothesized that baseline NT-pro-BNP levels may get significantly increased in patients with inducible ischemia by DSE and might serve as a clinical marker of inducible ischemia.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
Patients
A total of 143 consecutive patients referred for DSE study were enrolled in this study. Fifteen patients were excluded from the study due to a poor acoustic window (n=11) or failure to comply with blood sampling (n=4), thus leaving a total of 128 patients included in the analysis.

Study protocol
Detailed medical history was obtained from all patients submitted to DSE study and the presence of any of the conventional coronary artery disease risk factors was recorded: age, diabetes mellitus, hypertension, hypercholesterolemia, smoking, previous history of coronary artery disease, myocardial infarction, percutaneous coronary intervention (PCI), and coronary artery by pass grafting (CABG). Blood samples were drawn immediately before and 1h after the termination of dobutamine infusion. The study was approved by our Institutional Review Board and all patients provided a written, informed consent.

NT-pro-BNP measurements
Venous blood samples were drawn from all individuals of our study, after 12h fasting and centrifuged at 4000xg for 8min. The separated serum was then stored and frozen at –80°C, until analysis 7–30 days after blood sampling. Baseline and post-DSE blood samples were analyzed for NT-pro-BNP using an electrochemoluminescent immunoassay (Roche Diagnostics, Indianapolis, Indiana) on an Elecsys 1010 autoanalyzer. Coefficients of variation for the assays were 1.3–2.4%. Normal values of NT-pro-BNP serum levels in our laboratory are <100pg/ml.

Echocardiography
Endocardial border detection was achieved with the use of second harmonic imaging. Left ventricular end-diastolic diameter (LVEDD), left ventricular end-systolic diameter (LVESD), interventricular septum (IVS), posterior wall (PW) and left ventricular ejection fraction (LVEF) were measured according to standard techniques.14 Hypertrophy of the LV was defined by interventricular septum>12mm. Diastolic dysfunction was defined according to echo findings: transmitral flow velocity E<A, prolonged deceleration time (>250ms) and ratio of transmitral flow velocity E to diastolic velocity e of mitral annulus (assessed by pulsed tissue doppler imaging)>16. Qualitative evaluation of LV systolic function was based on the division of the LV into 16 segments, according to the proposed model by the American Society of Echocardiography.15 Segmental wall motion was characterized as normal, hypokinetic, akinetic or dyskinetic. A segment was considered to be hypokinetic or akinetic when endocardial excursion was <5mm and <2mm, respectively. Systolic blood pressure (SBP) was measured before DSE and at the time of termination of the dobutamine infusion. Systolic wall stress (WS) before DSE and at the time of termination of the dobutamine infusion was calculated according to the formula of Grossman et al.16: WS=0.334xSBPxLVESD/PWs(1+PWs/LVESD), where SBP is systolic blood pressure in mmHg, LVESD is left ventricular end-systolic diameter and PWs is posterior wall thickness at end systole.

Stress echocardiography
Stress echocardiography was performed with dobutamine–atropine infusion. Dobutamine was infused at incremental doses of 5, 10, 20 30, 40 and 50µg/kg per min in 3-min stages.15 Target heart rate was 90% of the predicted maximal heart rate according to age. If target heart rate was not achieved after accomplishing the 5th stage of DSE study, atropine (0.5–2mg) was additionally administered intravenously. Dobutamine infusion was stopped when one of the following criteria was met: maximal heart rate reaches 90% of the predicted maximal heart rate according to age, abnormal myocardial thickening or motion appeared in new regions, arterial blood pressure>240/120mmHg or lowering of systolic blood pressure<90mmHg accompanied by severe symptoms, sustained ventricular tachycardia, and ECG changes indicative of myocardial ischemia (ST segment elevation≥1mm) with coexisting abnormal myocardial thickening.17,18 Beta-blockers, diltiazem, and verapamil were discontinued 3 days before DSE study.

Two-dimensional echocardiography was performed in the parasternal long- and short-axis views and apical 4- and 2-chamber views, while 12-lead ECG and blood pressure was continuously recorded. The left ventricle was divided into 16 segments, which were further studied regarding their systolic thickening, according to the relevant guidelines approved by the American Society of Echocardiography.15 Every studied segment was characterized as normal, hypokinetic, akinetic or dyskinetic. Myocardial ischemia was documented by the presence of either ischemic (reduced systolic thickening of a segment with previously normal thickening in response to dobutamine infusion) or biphasic response (improved systolic thickening of a previous hypokinetic/akinetic segment in response to initially low dosage, and following deterioration in response to higher rates of dobutamine infusion). Reduced systolic thickening of a previous hypokinetic segment and absence of hyperdynamic response (systolic thickening<75% of diastolic thickness) of a segment with previously normal thickening in response to dobutamine infusion were additional criteria indicative of myocardial ischemia. Severe DSE-induced ischemia was defined as detected myocardial ischemia in 5 or more myocardial segments, in 16 myocardial segments model according to ACC/AHA (ischemia>30% of mass of myocardial tissue).

All echo studies were digitalized and stored as DivX 5 files, and were further analyzed later by two experienced cardiologists. All echo measurements for all patients were considered as mean value of the measurements performed by the two cardiologists separately. Interobserver variability of the two cardiologists was <5%, whereas intraobserver variability was <4% for both of them. Regarding DSE studies, kappa coefficient was found to be as high as 0.93 (p=0.001). In cases of discordances between the two cardiologists regarding thickening of myocardial regions, a common final decision was taken after reviewing together the cases again.

Statistical methods
Numerical variables were presented as mean±SE, and discrete variables were summarized by percentages. Comparisons of continuous variables between groups were performed with the non-parametric Mann–Whitney U-test. Pre–post-comparisons with paired observations of continuous variables were analyzed by using the Wilcoxon test. Linear regression analyses were performed to examine for predictors of dependent continuous variables (NT-pro-BNP levels). Logistic regression analyses were used in order to investigate for predictors of dependent dichotomous variables (DSE-induced ischemia). Regarding multivariate analyses, we used in all cases stepwise models. Receiver operating characteristic (ROC) curves were calculated to assess the value of NT-pro-BNP serum levels before and after DSE study for identifying DSE-induced ischemia. Regarding echo measurements, interobserver and intraobserver variabilities were expressed as the coefficient of variation within subjects, after applying one-way analysis of variance (ANOVA). Regarding DSE studies, inter-rater reliability was assessed by estimating kappa coefficient as a measure of agreement. p-Value<0.05 was considered statistically significant. All analyses were performed using SPSS 7.0 (SPSS, Inc., Chicago, IL, USA).


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Baseline characteristics
Clinical characteristics of 128 study participants, aged 55.54±11.49 years, are shown in Table 1. All study participants had normal renal function (creatinine serum levels<1.2mg/dl). Thirty-six (28.1%) patients had a DSE study indicative of myocardial ischemia (26 patients had mild or moderate DSE inducible ischemia, whereas the rest 10 patients had severe ischemia). The two groups of patients with and without inducible ischemia after DSE had similar baseline characteristics, as shown in Table 2. However, the group of 10 participants with severe DSE inducible ischemia, as compared to patients with mild or moderate DSE inducible ischemia and patients without DSE inducible ischemia, had significantly larger LVEDD (53.9±8.6 vs. 48.5±6.1 vs. 47±5.32, respectively, p=0.05 and p=0.04, respectively), larger LVESD (41.5±9.7 vs. 32.7±5.8 vs. 31.2±6, respectively, p=0.04 and p=0.006, respectively), and lower ejection fraction (45.8±14.2% vs. 55.7±14.7% vs. 57±11% respectively, p=0.05 and p=0.01, respectively).


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  		Table 1 Patient characteristics (n=128)

 


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  		Table 2 Clinical characteristics and NT-pro-BNP levels of patients with and without inducible ischemia during dobutamine stress echocardiography

 
Systolic wall stress
Systolic wall stress before DSE (baseline) was not different between patients with and without DSE inducible ischemia (47.77±10.92mmHg vs. 47.59±11.58mmHg, p=NS). However, systolic wall stress at the time of termination of dobutamine infusion was significantly higher in patients with DSE inducible ischemia (55.3±26.25mmHg) as compared to patients without (41.79±19.43mmHg, p=0.04). A non-significant reduction of wall stress at the time of termination of dobutamine infusion as compared to baseline was identified in patients without DSE inducible ischemia (41.79±19.43mmHg vs. 47.59±11.58mmHg, respectively, p=0.22). Similarly, patients with inducible ischemia experienced a non-significant increase of wall stress at the time of termination of the dobutamine infusion as compared to baseline (55.3±26.25 vs. 47.77±10.92, respectively, p=0.06).

NT-pro-BNP levels
NT-pro-BNP levels were similar before and after DSE regardless of whether patients had (123±101.8pg/ml median=87.27pg/ml vs. 124.2±108.3pg/ml median=80.69pg/ml, p=NS) or did not have inducible ischemia (96.5±70.5pg/ml median=94.02pg/ml vs. 100.5±71.1pg/ml median=100.14pg/ml, p=NS) (Fig. 1A). Patients with mild or moderate DSE inducible ischemia had also similar NT-pro-BNP levels before and after DSE study (96±78.9pg/ml median=64.82pg/ml vs. 94.8±81.1pg/ml median=68.49pg/ml, p=NS), as well as patients with severe DSE inducible ischemia (208.5±125.5pg/ml median=202.8pg/ml vs. 212.5±138.1pg/ml median=156.85pg/ml, p=NS) (Fig. 1B). Differences of NT-pro-BNP serum levels pre- and post-DSE studies were also similar between patients without ischemia, mild or moderate, and severe inducible DSE ischemia (3.9±17.6pg/ml vs. 1.4±13.8pg/ml vs. 4±52.5pg/ml, respectively, p=NS).


Figure 1
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  		Figure 1 NT-pro-BNP levels before and after dobutamine stress echocardiography (DSE) in patients with and without DSE-induced ischemia (A), and with mild/moderate and severe ischemia (B) (means, 95% confidence interval).

 
Patients with inducible myocardial ischemia had no different NT-pro-BNP levels as compared to patients without inducible ischemia both before and after DSE (Table 2). However, the subgroup of 10 patients with severe inducible ischemia was found to have significantly higher NT-pro-BNP levels as compared to patients with mild or moderate inducible ischemia and patients without inducible ischemia, both before (208.5±125.5 vs. 96±78.9 vs. 96.5±70pg/ml, respectively, p=0.017 and p=0.025, respectively, Fig. 2A) and after DSE (212.5±138.1 vs. 94.8±81.1 vs. 100.5±71.1pg/ml, respectively, p=0.015 and p=0.023, respectively, Fig. 2B).


Figure 2
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  		Figure 2 NT-pro-BNP levels in patients with no inducible ischemia, mild/moderate and severe ischemia before (A) and after (B) dobutamine stress echocardiography (DSE) (means, 95% confidence interval).

 
NT-pro-BNP levels both at baseline and after DSE were found to be significantly correlated to age (r=0.503, p<0.0001 and r=0.469, p<0.0001, respectively), and left ventricular ejection fraction (r=–0.276, p=0.009 and r=–0.319, p=0.002, respectively) (Fig. 3). NT-pro-BNP levels at baseline did not correlate with baseline systolic wall stress (r=0.1, p=0.4). Moreover, NT-pro-BNP levels after DSE did not correlate with systolic wall stress at termination of the dobutamine infusion (r=0.11, p=0.36). Finally, baseline ratio E/e did not correlate with baseline NT-pro-BNP levels (p=NS).


Figure 3
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  		Figure 3 Correlation of NT-pro-BNP with age before and after dobutamine stress echocardiography (DSE).

 
Subgroup analyses
We compared the levels of NT-pro-BNP in various subgroups of the study population. Patients with known coronary artery disease had significantly higher levels of NT-pro-BNP compared to patients without known coronary artery disease, both at baseline (138±88 vs. 90.2±66.1, p=0.001) and after DSE (133.6±79.2 vs. 88.4±71.6, p=0.003). This was also true for patients with vs. patients without myocardial infarction (158.4±95.7 vs. 96.9±67.8, p=0.01) at baseline and after DSE (172±110.5 vs. 96.4±60.6, p=0.004), and diabetics vs. patients without diabetes (168.2±102.4 vs. 92.5±63.4, p=0.008) at baseline and (171.7±111.8 vs. 95±63.2, p=0.01) and after DSE. However, DSE failed to produce any significant change in NT-pro-BNP levels in any of these two subgroups (p=NS). Moreover, patients with normal ejection fraction (>50%) and no inducible ischemia (N=65) did not have any significant change in NT-pro-BNP levels (120.7±141.9 vs. 125.4±147.5, p=NS), as well as patients with normal ejection fraction (>50%) but with inducible ischemia (N=27) (154.3±184.7 vs. 158.2±184.8, p=NS). Patients with impaired ejection fraction (<50%) and no inducible ischemia (N=19) did not have any significant change in NT-pro-BNP levels (251.1±234.2 vs. 274.1±256.1, p=NS), as well as patients with impaired ejection fraction (<50%) but with inducible ischemia (N=17) (202.7±169.2 vs. 200.9±161.6, p=NS). In patients without DSE inducible ischemia NT-pro-BNP levels both at baseline and after DSE correlated significantly with age (r=0.53, p<0.0001 and r=0.53, p<0.0001, respectively), and left ventricular ejection fraction (r=–0.37, p=0.003 and r=–0.45, p<0.0001, respectively). NT-pro-BNP levels at baseline did not correlate with baseline systolic wall stress (r=–0.04, p=0.74) in this subgroup of patients. Similarly, NT-pro-BNP levels after DSE did not correlate with systolic wall stress at termination of the dobutamine infusion (r=0.07, p=0.6).

In patients with DSE inducible ischemia, NT-pro-BNP levels both at baseline and after DSE correlated significantly only with age (r=0.45, p=0.02 and r=0.4, p=0.05, respectively), and left ventricular ejection fraction (r=–0.37, p=0.003 and r=–0.45, p<0.0001, respectively). NT-pro-BNP levels at baseline did not correlate with baseline systolic wall stress (r=35, p=0.16) in this subgroup of patients. Similarly, NT-pro-BNP levels after DSE did not correlate with systolic wall stress at termination of the dobutamine infusion (r=0.17, p=0.51).

Multivariate analyses to predict NT-pro-BNP levels
Multivariate stepwise linear regression analysis revealed that NT-pro-BNP levels before DSE could be independently predicted by age (β=2.59 95%C.I.=1.2–3.9, p<0.0001), presence of diabetes mellitus (β=62.07 95%C.I.=22.7–101.3, p=0.002), and ejection fraction (β=–3.31 95%C.I.=–5.6 to –1.02, p=0.005), but not by DSE-induced ischemia (p=0.36), sex (p=0.64), presence of hypertension (p=0.08), presence of hyperlipidemia (p=0.55), diastolic dysfunction (p=0.32) and LVEDD (p=0.57) (Model's statistics: R=0.64, R2=0.4, F=15.3, p<0.0001). Similarly, using multivariate stepwise linear regression analysis, we found that age (β=2.3 95%C.I.=0.84–3.8, p=0.003), presence of diabetes mellitus (β=56.9 95%C.I.=14.7–99.1, p=0.009), and ejection fraction (β=–4.3 95%C.I.=–6.8 to –1.8, p=0.001) are also independent predictors of NT-pro-BNP levels post-DSE after examining with DSE-induced ischemia (p=0.75), sex (p=0.69), presence of hypertension (p=0.26), presence of hyperlipidemia (p=0.43), diastolic dysfunction (p=0.77) and LVEDD (p=0.47) (Model's statistics: R=0.64, R2=0.41, F=14.3, p<0.0001).

Logistic regression analysis showed that DSE inducible ischemia could not be predicted by age, sex, NT-pro-BNP levels both baseline and post-DSE, ejection fraction, LVEDD, presence of diabetes mellitus, hypertension, hyperlipidemia and diastolic dysfunction. Only severe DSE inducible ischemia was found to be independently predicted by NT-pro-BNP levels before (exp(B)=1.01 95%C.I.=1.003–1.02, p=0.01) and after DSE study (exp(B)=1.009 95%C.I.=1.0004–1.01, p=0.04), after examining with age, sex, ejection fraction, LVEDD, presence of diabetes mellitus, hypertension, hyperlipidemia and diastolic dysfunction.

Receiver operating characteristic (ROC) curves
The ROC curve of NT-pro-BNP serum levels obtained both before and after DSE study showed no value in discriminating DSE-induced ischemia (area under the curve=0.56 95%C.I.=0.42–0.69, standard error=0.06, p=0.37 and area under the curve=0.54 95%C.I.=0.39–0.68, standard error=0.07, p=0.55, respectively). However, the ROC curve of NT-pro-BNP serum levels showed medium value in discriminating severe DSE-induced ischemia obtained both before DSE study (area under the curve=0.78 95%C.I.=0.61–0.95, standard error=0.08, p=0.01), and after DSE study (area under the curve=0.79 95%C.I.=0.63–0.95, standard error=0.08, p=0.01). Finally, ROC curve of NT-pro-BNP serum levels obtained both before and after DSE study showed good value in discriminating amongst patients with DSE-induced ischemia those with severe ischemia (area under the curve=0.82 95%C.I.=0.64–0.99, standard error=0.08, p=0.02 and area under the curve=0.82 95%C.I.=0.66–0.99, standard error=0.08, p=0.01, respectively).


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
Although there have been reports examining changes of NT-pro-BNP serum levels during exercise,10–12,19,20 this is the first study that addressed the effect of DSE on NT-pro-BNP serum levels. There are four major findings of our study. First, DSE inducible ischemia does not affect serum levels of NT-pro-BNP, regardless of the severity of DSE inducible myocardial ischemia. Second, both baseline and post-DSE study serum levels of NT-pro-BNP are higher only in the subgroup of patients with demonstrated severe ischemia during DSE. Our findings suggest that patients with severe DSE-induced ischemia have higher serum levels of NT-pro-BNP (both pre- and post-DSE studies) as compared to patients with mild/moderate and without ischemia, but inducible ischemia does not increase serum levels of NT-pro-BNP in any subgroup of patients. Third, levels of NT-pro-BNP cannot predict DSE-inducible myocardial ischemia in general; they can only predict severe DSE inducible ischemia. Fourth, age and diabetes mellitus – as well as left ventricular ejection fraction – are independent predictors of serum levels of NT-pro-BNP.

Earlier studies have provided the evidence of increased ANP and BNP serum levels after exercise in patients with a history of myocardial infarction or stable coronary artery disease.19,20 However, recent studies that examined alterations of NT-pro-BNP serum levels due to exercise-induced myocardial ischemia in such patients resulted in inconsistent findings. Sabatine et al.11 failed to demonstrate that exercise-induced myocardial ischemia affects NT-pro-BNP serum levels even after subgroup analysis according to the severity of provoked ischemia. They only showed an increase of NT-pro-BNP serum levels in patients with inducible ischemia, which, however, did not reach any statistical significance. Weber et al.10 also failed to demonstrate any significant change of NT-pro-BNP serum levels after exercise in patients with a treadmill stress test positive for myocardial ischemia. Foote et al.12 reported that the absolute increases of NT-pro-BNP serum levels after exercise are more profound in patients with exercise-induced myocardial ischemia. In this study, recruited subjects with increased levels of NT-pro-BNP were excluded thus facilitating the detection of changes in NT-pro-BNP serum levels provoked by exercise. They demonstrated12 that the absolute increases of NT-pro-BNP serum levels in ischemic and non-ischemic groups of patients were only compared and found to be higher in patients with inducible ischemia. However, no data regarding NT-pro-BNP serum levels post stress test in all groups of patients were provided and no paired comparisons in each subgroup were performed. The appropriate timing for blood sampling in order to detect exercise-induced differences in NT-pro-BNP serum levels after exercise has not been determined. In one study,12 patients were blood sampled at 1min, whereas in another11 at 7min and at 4h after exercise. In the latter study, 4h following exercise patients had NT-pro-BNP serum levels approximately similar to baseline. Taking into consideration the half-life of NT-pro-BNP (2–3h),20,21 we thought that 60min following DSE study must be a reasonable time point for blood sampling. It seems, therefore, that the effect of exercise on NT-pro-BNP levels is profound only when significant myocardial ischemia is evoked.

It has been proposed that myocardial ischemia augments the synthesis and release of BNP, even in the absence of necrosis or preexisting left ventricular dysfunction.22,23 Transient myocardial ischemia induced during uncomplicated percutaneous coronary angioplasty may also cause increased BNP serum levels after it.24 However, a direct correlation between wall stress and BNP serum levels has not been examined so far, in patients with myocardial ischemia. BNP release constitutes a feedback mechanism for regulation (reduction) of ventricular wall stress.25 Wall stress is proportional to pressure and ventricular internal dimensions and is inversely related to thickness of myocardial wall. During episodes of myocardial ischemia at rest both dimensions of ventricular cavities and left ventricular end-diastolic pressure are elevated and therefore wall stress increases, which contributes to increased oxygen debt.21,25 Therefore, we could speculate that during exercise or dobutamine stress induced ischemia, the effects of exercise or dobutamine stress on dimensions of ventricular cavities (reduction) and thickness of myocardial wall (increase) counteract the corresponding results due to ischemia (increase and reduction, respectively), thus not changing net wall stress. In the case of DSE, this is further supported by the fact that the arterial systolic pressure remains usually unchanged or slightly decreased. In this study, it has been demonstrated that no statistical significant change of systolic wall stress took place after DSE in the groups of patients with or without DSE inducible ischemia. However, no correlation between NT-pro-BNP levels and systolic wall stress was identified in patients with or without DSE inducible ischemia, both before and after the DSE study. Only patients with severe ischemia, defined as more than 5 myocardial segments which actually represents >30% of myocardial mass, had significantly higher NT-pro-BNP serum levels, both pre- and post-DSE studies, as compared to patients with mild or moderate ischemia or without ischemia. These patients had higher left ventricular diastolic and systolic dimensions and lower ejection fraction.

In most published studies with patients with coronary artery disease or heart failure, age has not been considered as a possible factor that may affect BNP or NT-pro-BNP serum levels and thus not have been included in any statistic model. In our study, we have provided the evidence of a significant linear correlation between age and NT-pro-BNP serum levels and we have demonstrated that the age is an independent predictor of NT-pro-BNP serum levels, regardless of induced DSE ischemia. Aging may affect elastic properties of myocardial muscle,26 thus causing increases of wall stress and secretion of NT-pro-BNP serum levels. Moreover, hypertension or diastolic dysfunction, which are more frequent among older patients, may contribute to increases of wall stress in older patients. In the study of Foote et al.,12 the demonstrated larger absolute increase of NT-pro-BNP serum levels in patients with ischemia may be attributed to the higher percentage of older patients.

Diabetes mellitus was found to be another independent predictor of NT-pro-BNP serum levels in this study. Our findings are consistent with those of Weber et al.,10 who found that patients with stable angina pectoris and diabetes mellitus have higher NT-pro-BNP serum levels as compared to non-diabetics. Diabetes mellitus is known to cause impairment of myocardial relaxation27 as well as endothelial dysfunction28 in coronary arterioles and subendocardial ischemia, even in the absence of ventricular hypertrophy or significant epicardial coronary artery stenosis. A previous study has documented that BNP serum levels possess a significant prognostic role in diabetic patients, regarding cardiac and all cause mortality.29

A limitation of our study might be the lack of BNP serum levels data. However, NT-pro-BNP has longer half-life20,21 compared to BNP (2–3h vs. 18min), which may imply that acute changes in serum levels may be more persistent and thus more easily detectable in clinical practice. From this point of view NT-pro-BNP serum levels may be a more clinically suitable way of assessing wall stress than BNP serum levels. In addition, there has been evidence that natriuretic peptides might have different responses to exercise in different subsets of patients.11 In an earlier study with patients with heart failure, both N-terminal proatrial natriuretic peptide and N-terminal probrain natriuretic peptide increased at peak exercise but less than their C-terminal counterparts.20 Another limitation of our study could be the small number of patients with induced ischemia enrolled, only 36, that might imply that no identifiable difference regarding NT-pro-BNP serum levels during stress echo in these patients could be attributed to a type II error. However, a previous study12 which has shown increase of BNP and NT-pro-BNP serum levels in patients with exercise-induced myocardial ischemia enrolled almost the same number of patients (40 patients).

In summary, our study indicated that DSE-induced ischemia is not accompanied by elevations of NT-pro-BNP serum levels, regardless of the severity of ischemia. Age, diabetes mellitus and left ventricular ejection fraction are independent predictors of NT-pro-BNP serum levels, and should be taken into account in everyday clinical practice when interpreting data with natriuretic peptides. Severe myocardial ischemia is accompanied by higher NT-pro-BNP serum levels, even though not further raised when ischemia is induced with a dobutamine stress echo study. Thus, NT-pro-BNP serum levels cannot be used in clinical practice to improve the accuracy of DSE study when performed for the detection of myocardial ischemia.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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