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ORIGINAL ARTICLE

Comparison of Pro B-natriuretic Peptide in Hypertensive Patients with and without Diastolic DysfunctionYudistira P. Santosa*, Anna Tjandrawati**, Noormartany**, Erwinanto***, Ahmad F. Yahya***, Erwan Martanto***, Pintoko Tedjokusumo***, Augustine Purnomowati***, Eko Antono***

* Department of Internal Medicine, Faculty of Medicine Atmajaya University, Jl. Pluit Raya no. 2, Jakarta. E-mail: yudipsan@yahoo.com,** Department of Clinical Pathology, Medical Faculty of Padjadjaran University, Bandung,*** Department of Internal medicine, Medical Faculty of Padjadjaran University, Bandung,

ABSTRACTAim: to evaluate whether pro BNP can be used for

detection of diastolic dysfunction..Methods: thirty nine hypertensive patients with normal

systolic function, consecutively referred for echocardiography

examination between October and December 2004 were recruited in the study. Diastolic dysfunction was diagnosed when echocardiographic mitral ow pattern demonstrated impaired relaxation, pseudonormalization or restrictive like patterns. NT-pro BNP levels were assessed using electro chemiluminescence Immunoassay (ECLIA) method. Unpaired t test was used to analyze the results.

Results: twelve out of thirty nine subjects had normal diastolic function. All base line characteristics, except for uric acid, were equally distributed between normal and abnormal diastolic function group. NT-pro BNP levels were nearly signicantly higher in the diastolic dysfunction group (P=0.053).

Conclusion: NT-pro BNP levels trends to be higher in hypertensive subjects with diastolic dysfunction.

Key words: hypertension, pro B-Natriuretic peptide, diastolic dysfunction.

INTRODUCTIONHypertensive patients may present with normal or

abnormal diastolic function. The distinction between these two conditions is important because diastolic dysfunc-tion may be associated with worse long-term survival. Hypertensive patients with abnormal left ventricular lling patterns suggestive of diastolic dysfunction may be asymptomatic but often report exertional dyspnea.1,2 Thus, it is very important to detect diastolic dysfunction earlier to prevent diastolic heart failure.

Diastolic dysfunction can be detected with cardiac catheterization. Because this is an invasive procedure other modalities are needed. NT-Pro B-natriuretic peptide (NT pro-BNP) is a cardiac neurohormone secreted from the ventricles in response to ventricular volume expansion and pressure overload.3,4 Pro BNP levels are known to be elevated in patients with symptomatic LV dysfunction and correlate to NYHA class and prognosis.5-9 BNP levels may also reflect

diastolic dysfunction.10,11 This study was aimed to evaluate whether pro BNP can be used for detection of diastolic dysfunction.

METHODS

Study PopulationThe study was done in the Hypertensive Out patient

Clinic at Hasan Sadikin Hospital, Bandung, Indonesia. A sample of 39 patients who were consecutively referred for echocardiography to evaluate LV function at the Non-invasive Cardiology Division between October and December 2004. Twenty one patients with an ejection fraction <50% or an LV end-diastolic dimension >5.5 mm were excluded.

EchocardiographyM-mode and 2D images and spectral and color ow

Doppler recordings were obtained with commercially available instruments operating at 2.0 to 3.5 MHz. Two-dimensional imaging examinations were performed in the standard fashion in parasternal long- and short-axis views and apical 4- and 2-chamber views. Pulsed Doppler spectral recordings were obtained in the apical 4-chamber view from a 4x4-mm sample volume positioned at the tips of the mitral leaets and in the right upper paraseptal pulmonary vein and adjusted to yield velocity signals of maximal amplitude. Left atrial and LV dimensions were measured from M-mode images according to standard criteria. The transmitral pulsed Doppler velocity recordings from 3 consecutive cardiac cycles were used

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Yudistira P. Santosa, et al Acta Med Indones-Indones J Intern Med

to derive measurements as follows: E and A velocities were the peak values reached in early diastole and after atrial contraction, respectively, and deceleration time

(DT) was the interval from the E-wave peak to the decline of the velocity to baseline. In those cases in which velocity did not return to baseline, extrapolation of the deceleration signal was performed. In addition, pulmonary venous systolic and diastolic ow velocities were obtained as the maximal values reached during the respective phase of the cardiac cycle, and the pulmonary venous “A” reversal was the maximal velocity of retrograde ow into the vein after the P wave of the ECG. Finally, the LV isovolumetric relaxation time (IVRT) was obtained in the apical 5-chamber view with a continuous-wave cursor or, if possible, a pulsed Doppler sample volume positioned to straddle the LV outflow tract and mitral orifice to obtain signals from aortic valve closure, the termination of ejection and mitral valve opening, or the onset of transmitral flow. IVRT was taken as the time in milliseconds from the end of ejection to the onset of LV lling.12 All echocardiograms were interpreted by four cardiologists who were blinded to the NT-proBNP levels.

Echo Classication

Normal Ventricular Function. Normal ventricular function was dened by normal LV end-diastolic (3.5 to 5.5 cm) and end-systolic (2.5 to 3.6 cm) dimensions, no major wall motion abnormalities, an ejection fraction >50%, and no evidence of impaired or restrictive like relaxation abnormalities as described below.12

Systolic Dysfunction. Systolic dysfunction was dened by an ejection fraction <50% or any wall motion abnormalities.12 Patients with systolic dysfunction

were excluded.

Diastolic Dysfunction.13, 14 Diastolic dysfunction was classied into 3 categories.

• Stage I : Impaired Relaxation Impaired relaxation was dened as an E/A ratio <1

or DT >240 ms in patients <55 years of age and an E/A ratio <0.8 and DT >240 ms in patients 55 years of age.

• Stage II: Pseudo normalization pattern Pseudo normal was dened as an E/A ratio of 1

to 1.5 and DT >240 ms. Confirmation included PVd/PVs >1.5 or IVRT <90 ms or by reversal of the E/A ratio (to <1.0) by Valsalva when possible.

• Stage III : Restrictive- like pattern Restrictive-like lling patterns were dened as DT

<160 ms with 1 of the following: left atrial size >5 cm, E/A >1.5, IVRT <70 ms, PVd/PVs >1.5, and

pulmonary “A” reversal duration exceeding forward mitral A-wave duration.

Chamber Abnormalities. Left atrial enlargement was dened as left atrial size > 5.0 cm. LV hypertrophy was dened as mean LV wall thickness of septum and posterior wall >1.2 cm.12 Patients with hypertrophiccardiomyopathy were excluded.

Measurement of NT-pro BNP LevelsAll samples were collected by venipuncture where

after the sample was centrifuged and plasma was removed, allocated, and frozen at -70°C before analy-sis. NT-Pro BNP level was analyzed with electro chemiluminescence Immunoassay “ECLIA” using the Roche Elecsys 1010/2010 and Modular Analytic E179 (Elecsys module) immunoassay.

Statistical AnalysisGroup comparisons of NT-pro BNP values were

made by use of unpaired t tests for independent samples and correlation between NT-Pro BNP levels with diastolic function. A multivariate approach for evaluat-ing the ability of NT-proBNP to identify diastolic dysfunction over and above the information provided by other indicators. To produce odds ratios, cut points were used for NT-pro BNP (125 pg/mL) to reduce them to nominal variables. Data were statistically analyzed with SPSS 10.0 software. All probabilities were two tailed and p < 0.05 was regarded as signicant.

RESULTS Patients were divided into 2 groups on the basis of

whether they showed normal or abnormal LV diastolic function by echocardiography. The baseline characteristics of the patients are shown in table 1. Most subjects were female (66.67%), both normal diastolic function and diastolic dysfunction groups. Most of patients had suffered from hypertension for two years and taken more than one antihypertensive drugs. All Baseline characteristics except for uric acid were equally distributed between normal and abnormal diastolic function groups.

NT-pro BNP Levels and Diastolic DysfunctionIt is shown in table 2 that the NT-pro BNP was higher

in the diastolic dysfunction group (103 + 99.51 pg/ml) compared to normal subject (66.21 + 41.22 pg/ml), but the difference between the two groups was not statisticaly signicant.

To produce ORs, cut points were used for NT-proBNP (125 pg/mL) to reduce them to nominal variables. The results are summarized in Table 2. Creatinine and sex (female) had correlation with higher BNP ((P=0.05) and (P=0.015)).

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Vol 40 • Number 1 • January 2008 Comparison of Pro B-natriuretic Peptide in Hypertensive Patients

Figure 1. Box and whisker plots of NT-pro BNP levels with diastolic dysfunction

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Yudistira P. Santosa, et al Acta Med Indones-Indones J Intern Med

DISCUSSIONAt present, measurements of serum levels of

neurohormone B-type natriuretic peptide have evolved into an important blood test in the diagnosis and treatment of congestive heart failure, and now possibly diastolic heart failure.14 Release of B-type natriuretic peptide is proportional to ventricular volume expansion and pressure overload and is an independent predictor of elevated left ventricular pressure.15 Lubien et al found that elevated levels of the peptide were accurate indicator of diastolic abnormalities detected by echocardiography regardless of patient’s history or signs and symptoms of congestive heart failure.16 Cheung shown that plasma BNP is increased to a greater extent in newly diagnosed untreated hypertensive patients with left ventricular hypertrophy and have evidence of diastolic dysfunction.10 Talwar et al found that the presence of hypertension with or without LVH (and normal left ventricular systolic function) does not affect NT proBNP concentrations. Moreover, there is a signicant rise in NT proBNP only when left ventricular systolic dysfunction develops in hypertension.17

In this study, we want to show the NT-proBNP level in hypertensive patients with diastolic dysfunction. We nd that NT-proBNP levels trends to be higher in hypertensive subjects with diastolic dysfunction but nearly signicant. Hypertensive patients used in this study were taking more than one antihypertensive drugs. Use of antihypertensive drugs can alter BNP concentrations. Beta-blockade, ACE inhibitors and diuretics may have variable effect on circulating BNP concentrations.18,19

Natriuretic peptides are increased in patients with increase creatinine concentration and regulated or modified by several physiologic factors, such as circadian variations, age, gender, exercise, body posture, and water immersion; eating habits, especially sodium intake.20 In this study, higher NT-pro BNP levels was associated with serum creatinine level and gender.

Pro-BNP cannot be used alone in diagnostic tests; it must be used and interpreted in a wider clinical context.21

We recommended further studies in broader hypertensive populations at risk for altered diastolic function are needed for determination of the potential

role of these peptides in clinical practice.

CONCLUSIONNT-proBNP levels trend to be higher in hypertensive

patients with diastolic dysfunction, but further studies are needed to conrm the potential role of these peptides in clinical practice.

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