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European Journal of Echocardiography 2006 7(1):40-44; doi:10.1016/j.euje.2005.03.009
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Copyright © 2005, The European Society of Cardiology

The BNP assay does not identify mild left ventricular diastolic dysfunction in asymptomatic diabetic patients

R. Vallea,*, E. Bagolinb, C. Canalia, P. Giovinazzoa, S. Barroa, N. Aspromontec, E. Carbonierid and L. Milania

aHeart Failure Centre, Cardiology Unit, Ospedale Civile, Via Sauro 26, San Donà di Piave, I-30027, VE, Italy
bDiabetes Outclinic, Ospedale Civile, San Donà di Piave, Italy
cHeart Failure Centre, Cardiology Unit, Santo Spirito Hospital, Rome, Italy
dHeart Failure Centre, Cardiology Unit, San Bonifacio Hospital, Italy

Received 7 November 2004; received in revised form 14 March 2005; accepted after revision 28 March 2005.

* Corresponding author. Tel.: +39 421 227537; fax: +39 421 227521. robertovalle{at}libero.it


   Abstract
Top
 Abstract
Introduction
 Aims
 Materials and methods
 Results
 Discussion
 References
 
Aims We examined the usefulness of BNP for screening for left ventricular (LV) diastolic dysfunction in a sample of type 2 diabetic patients, without structural heart disorder, who have never presented symptoms or signs of heart failure (HF).

Methods and results Seventy-six consecutive patients admitted to the Outpatient Diabetes Clinic were studied. Blood samples were analyzed using the Triage BNP fluorescence immunoassay (Biosite Diagnostics, La Jolla, CA, USA). Echocardiography examinations were performed, with no knowledge of the BNP value. A total of 39 patients out of 76 (51%) were diagnosed with LV diastolic dysfunction and 23 (30%) with LV hypertrophy. Of the patients with LV diastolic dysfunction, impaired relaxation and pseudonormal pattern accounted for 97 and 3% of the cases, respectively. BNP levels among subjects with LV diastolic dysfunction (26±22pg/ml, n=39) were not significantly different from patients with normal LV function (24±23pg/ml, n=37pg/ml; Mann–Whitney U-test, Z=–0.4, n.s.).

Conclusions Our data confirm alarmingly high prevalence of LV diastolic dysfunction in asymptomatic individuals with diabetes. Identification of patients with preclinical diabetic cardiomyopathy should be a research and clinical priority. BNP levels cannot be used to detect mild LV diastolic dysfunction in this subset of patients, which requires Doppler echocardiography to be detected.

Keywords: Diastolic dysfunction; B-type natriuretic peptide; Diabetes mellitus


   Introduction
Top
 Abstract
 Introduction
Aims
 Materials and methods
 Results
 Discussion
 References
 
Patients with type 2 diabetes mellitus (DM) are affected by diabetic cardiomyopathy (DCM), a preclinical left ventricular (LV) diastolic dysfunction with preserved systolic function.1,4 DM is a well-recognized negative prognostic factor for morbidity and mortality for diabetic subjects with heart failure (HF).5–8 Hence there is a need, in diabetic patients, for identifying those with asymptomatic left ventricular diastolic dysfunction, at risk of developing clinical HF. LV diastolic dysfunction requires echocardiography to be diagnosed, but this test is not available for routine diagnostic screening,9 therefore alternative diagnostic procedures will be helpful. It has been recently demonstrated10 that B-type natriuretic peptide (BNP) may be a useful screening tool for LV diastolic and/or systolic dysfunction in the community of diabetic patients, confirming previous pilot reports.11–14


   Aims
Top
 Abstract
 Introduction
 Aims
Materials and methods
 Results
 Discussion
 References
 
The aim of our study was to examine the usefulness of BNP for screening for LV diastolic dysfunction in a sample of type 2 diabetic patients, without structural heart disorder, who have never presented symptoms or signs of HF.


   Materials and methods
Top
 Abstract
 Introduction
 Aims
 Materials and methods
Results
 Discussion
 References
 
Study population
We screened 79 consecutive patients admitted to the Outpatient Diabetes Clinic. In order to be eligible for the study, patients had to simultaneously meet the following inclusion criteria:

- high risk of cardiovascular events15;
- no symptoms suggestive of HF16;
- no previous diagnosis of heart failure or structural heart disorders, including ischaemic heart disease;
- normal LV systolic function, defined as an LV ejection fraction (LVEF) >50%, a normal LV end diastolic diameter, no major wall abnormalities, except for LV hypertrophy, on echocardiographic examination.

Three patients were excluded because they met ≥1 exclusion criterion on echocardiographic examination.

BNP assay
Blood samples were obtained from patients after 30min of bed rest. Samples were immediately analyzed using the Triage BNP fluorescence immunoassay (Biosite Diagnostics, La Jolla, CA, USA).

Doppler echocardiography
Echocardiography tests were carried out using a Vingmed System Five device. The LVEF was measured using Simpson's biplane method. Diastolic indexes were acquired over 10 consecutive beats using sweep speeds of 50 and 100cm/s. With pulsed-wave Doppler, we acquired transmitral flow using a 1–2mm sample volume placed at the mitral leaflet tips in the apical four-chamber view and pulmonary venous flow using a 4-mm sample volume placed in the right upper pulmonary vein (PV). All images were measured by experienced investigators, who were blind to the clinical and BNP data. Measurements were averaged over three cycles and from pulsed-wave Doppler included transmitral peak E and A velocities and early deceleration time (DT) and PV systolic (S), diastolic (D), and atrial reversal (AR) flows.17 The classification of diastolic function was a predefined modification of classifications used in prior studies13,17,18: (1) impaired relaxation with a normal pattern (E/A<1 and deceleration time (DT) >220ms in subjects aged <55 years or E/A<0.8 and deceleration time >220ms in subjects aged >55 years, PV S/D ratio >1, and AR<35cm/s); (2) pseudonormal (E/A 1–2, DT 150–220ms, PV S/D ratio<1, and AR >35cm/s); (3) restrictive (E/A >2, DT≤150ms, S/D ratio<1, and AR >35cm/s). In patients suffering from atrial fibrillation at the time of the echocardiogram, the diastolic function was classified as: (1) restrictive pattern (DT≤150ms) or (2) indeterminate (DT >150ms). LV hypertrophy was defined as LV mass indexed to a body surface area of >131gm–2 in men and 100gm–2 in women.19

Statistics
The data are expressed as mean±standard deviation. A P-value <0.05 was considered significant. Categorical data are presented as numbers (percent), and continuous data as means+standard deviation. We used the Mann–Whitney U-test for the comparisons between samples, while the association between variables was verified with Fisher's exact test. Univariate logistic regression analysis was used to examine the relation of BNP levels with the presence of LV diastolic dysfunction. An ROC (receiver-operated curve) was traced to test whether BNP values could be used to identify patients with LV diastolic dysfunction. Analyses were performed using SPSS software for Windows, release 12.0 (SPSS Inc., Chicago, USA).


   Results
Top
 Abstract
 Introduction
 Aims
 Materials and methods
 Results
Discussion
 References
 
The characteristics of the study patients are shown in Table 1. The median age was 61±7 years; 75% were men. They suffered by numerous comorbidities, particularly carotid atherosclerosis (28%), peripheral vessel atherosclerosis (20%), claudicatio intermittens (10%), and previous stroke/TIA (5%) (Table 1). All patients had type 2 diabetes.


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  		Table 1 Demographic, clinical, and instrumental characteristics of 76 asymptomatic diabetic patients

 
A total of 39 patients out of 76 (51%) were diagnosed with LV diastolic dysfunction and 23 (30%) with LV hypertrophy (Table 1). Of the patients with LV diastolic dysfunction, impaired relaxation accounted for 97% of the cases, and pseudonormal pattern for 3% (Table 1). Table 1 illustrates the demographic characteristics (clinical, laboratory and instrumental) of subjects identified as suffering from LV dysfunction, and the rest of the study sample. There was a statistical difference between patients with LV diastolic dysfunction and those without, in terms of more frequent presence of hypertension, left atrial dilatation, ACE-inhibitors and thiazide diuretics prescription (Table 1).

Among the study population, the mean BNP value was 25±22pg/ml. BNP levels were correlated significantly with serum creatinine (Spearman-Rho=0.28, n.s.), while no significant correlations were found between BNP and age or body mass index (Spearman-Rho=0.18, and 0.15, respectively; n.s.), probably due to the small sample size. BNP levels among subjects with LV diastolic dysfunction (26±22pg/ml, n=39) were not significantly different from patients with normal LV function (24±23pg/ml, n=37pg/ml; Mann–Whitney U-test, Z=–0.4, n.s.). Fig. 1 shows the receiver-operator characteristic curve for BNP in the diagnosis of LV diastolic dysfunction in the study population. The area under the curve was is 0.53, and the confidence interval 0.39–0.66. BNP levels did not differ in relation to the presence of LV hypertrophy, being 27±26 in patients with the latter vs 24±21pg/ml in the remaining diabetics (Mann–Whitney U-test, Z=–0.7, n.s.). Restriction of the analysis to patients with evidence of LV diastolic dysfunction and/or LV hypertrophy did not significantly increase sensitivity and specificity (AUC 0.54; CI: 0.40–0.67). Univariate regression did not find BNP levels as predictors of LV diastolic dysfunction.


Figure 1
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  		Figure 1 ROC (receiver operating curve) in 76 asymptomatic diabetic patients to compare the sensitivity/specificity of the BNP values with the presence of left ventricular diastolic dysfunction. The AUC (area under the curve) is 0.53 and the confidence interval 0.39–0.66.

 

   Discussion
Top
 Abstract
 Introduction
 Aims
 Materials and methods
 Results
 Discussion
References
 
Our study confirms that asymptomatic patients with type 2 DM, free of structural heart disorders, have high prevalence rates of subclinical LV diastolic dysfunction, with preserved systolic function.1–4 Mild LV diastolic dysfunction may be the first stage of diabetic cardiomyopathy.20,21 It has been recently reported that diabetes results in functional, biochemical, and morphologic myocardial abnormalities independent of hypertension and coronary heart disease, leading to impaired diastolic function and to clinical diastolic heart failure (DHF) (see22 for a review).

DHF is a disorder with a growing epidemiological impact, characterised by frequent episodes of instability, with high rates of mortality and admission to hospital (see23 for a review). Around 30% of patients with DHF have diabetes.22 Although it is still not clear whether any drug intervention changes the prognosis of DHF patients, other than hypertension control,24 diastolic function may be improved by aerobic exercise25 and angiotensin converting enzyme inhibitors26 and tight glycemic control decreases the risk of HF in individuals with diabetes.27 Hence there is a need, in diabetic patients, for identifying those with initial diastolic impairment.

Unfortunately, our data do not support a possible role of natriuretic peptides as a procedure for screening mild LV diastolic dysfunction in asymptomatic diabetic patients. Previous studies showed that patients with DM had high BNP levels along with left ventricular dysfunction.10–14 However, these studies included patients with both systolic and (even severe) diastolic dysfunction. In our sample of asymptomatic diabetic patients, impaired relaxation cannot be identified using BNP levels, probably due to no or slight elevation of the LV filling pressures. This is consistent with previous reports by Dahlstrom28 (in a sample of patients with isolated diastolic dysfunction and relaxation abnormalities), and Zhi29 (in a large sample of subjects with subclinical diastolic and/or systolic LV dysfunction).

This study has many limitations. It is a single center study, which enrolled a small sample. Furthermore, the parameters of diastolic function assessed are all highly load dependent and do not entirely reflect LV diastolic dysfunction.

In conclusion, our data confirm alarmingly high prevalence of LV diastolic dysfunction in asymptomatic individuals with diabetes. Identification of patients with preclinical DCM should be a research and clinical priority. BNP levels cannot be used to detect mild LV diastolic dysfunction in this subset of patients, which requires Doppler echocardiography to be detected.


   References
Top
 Abstract
 Introduction
 Aims
 Materials and methods
 Results
 Discussion
 References
 

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