B-TYPE NATRIURETIC PEPTIDE (PNP) CAN PREDICT SILENT

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AL_AZHAR ASSIUT MEDICAL JOURNAL AAMJ, VOL (12), NO (4), OCT 2014 SUPPL - 2

B-TYPE NATRIURETIC PEPTIDE (PNP) CAN PREDICT

SILENT MYOCARDIAL ISCHEMIA IN ASYMPTOMATIC

EGYPTIAN PATIENTS WITH TYPE 2 DIABETES MELLITUS.

Khaled Massoud Dessouky1, Kamal Hashem Salah

2

and Abdelaziz Rezk Sheridah3.

1Internal medicine, 2Clinical pathology and3Cardiology Departments, Faculty of

Medicine, Al-Azhar University.

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ABSTRACT

Background: B-type natriuretic peptide (BNP) is a hormone that is

released primarily by ventricular myocyte in response to physiological and

pathological stimuli. Many studies suggested that raised level of BNP in non-

heart failure may indicate coronary artery disease (CAD) particularly in high

risk groups. Aim of this study: is to determine whether BNP can predict

myocardial ischemia in asymptomatic Egyptian patients with type 2- diabetes

mellitus (DM) Patients and methods: 50 male patients with type 2 DM were

enrolled in this study. We excluded patients with history or evidence of heart

failure or coronary artery disease. All patients were subjected to history taking,

full clinical examination and laboratory tests: renal function, BNP, lipid profile,

HbA1c, Resting, exercise ECG testing and resting transthoracic 2D Doppler

Echocardiography. Results: Myocardial ischemia was found in 36 patients

(75%) by exercise ECG testing (positive group) While 12patients (12%) showed

normal Exercise testing (Normal group). 2 patients showed equivocal exercise

testing were excluded from the study. BNP level was significantly higher in

positive group compared to normal group (43.54 ± 9.6) vs (15.43±3.91) pg

/ml (P< 0.000). It was found that BNP level cut off > 22.4 pg / ml predicted

positive exercise ECG testing with sensitivity 88.89 % and specificity 75 % for

diagnosis of myocardial ischemia. CONCLUSION: BNP level is of value in

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Khaled Massoud Dessouky et al

AAMJ, VOL (12), NO (4), OCT 2014 SUPPL - 2

SUPLL - 2

predicting silent myocardial ischemia in asymptomatic Egyptian patients with

type 2- DM.

INTRODUCTION

The heart is now recognized as an endocrine organ. It released a number of

hormones, which belong to the natriuretic peptide family. There are currently

four types of natriuretic peptides that have been described as ANP , BNP, CNP,

and DNP . ANP and BNP are primarily released from heart (1) .

In human, BNP is primarily derived from the ventricular myocyte . It has

several systemic effects, which counteract CV volume overload including

vasodilatation, diuresis, and inhibition of the Renin- Angiotensin- Aldosterone

system (2).

BNP synthesis is constitutive and its release is triggered by variety of

physiological and pathological stimuli including CHF, both LV systolic and

diastolic dysfunction, LVH, vulvar heart disease, pulmonary, renal diseases and

advanced age (3).

The use of BNP in the diagnosis and prognosis of heart failure patient is

now well established (4). However, Evidence point towards a role of BNP in

identifying patients with myocardial ischemia and coronary artery disease

(CAD) (3)

BNP may also help to identify CAD in asymptomatic patients and this

particularly important because patients with silent myocardial ischemia have a

21 – fold increase risk of coronary event (5). In addition almost 50 % of sudden

cardiac death still occurs in people with no documented previous history of

overt Cardiac disease (6) .Therefore, screening high risk groups with this simple

blood test may be a logic approach. Diabetic patients are clear example of such

high risk patients as they are known to have high incidence of silent coronary

disease (7).

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The aim of this work is to determine whether BNP can predict silent

myocardial ischemia in asymptomatic Egyptian patients with type 2-DM .

PATIENTS AND METHODS

Fifty (50) male patients with type 2-diabetes mellitus were included in this

study. They were selected from outpatient DM clinic of Sayed Galal Al – Azhar

university hospital. The study was performed during the period from October

2013 to March 2015, after departmental ethical committee approval and patients

consents were obtained , all patients were male to avoid possible fallacies with

female gender (estrogen related) and on regular anti-diabetic therapy.

Exclusion criteria:

Females, patients suggested to have myocardial ischemia and those

known to have CAD or undergone coronary intervention. Patients with evidence

of left ventricular hypertrophy (LVH) , heart failure, LVH with ejection fraction

< 50% on transthoracic echocardiography. Patients with serum creatinin >1.2

mg /dl and patients who had parenchymal or pulmonary vascular disease.

Methods: All participants were subjected to:

1-Full history taking with special emphasis on duration of diabetes

mellitus, history of documented CAD, PCI or CABAG

2-Full clinical examination with special stress on complete cardiac

examination, body mass index ( BMI) and waist circumference ( WC).

3-Laboratory Investigations:

Renal function tests including blood urea and serum creatinine . Were

measured by enzymatic colorimetric assay, using Hitachi 911 automatic

analyzer .

Lipid profile including: Total cholesterol ( TC), triglyceride (TG),

High density lipoprotein (HDL-C ) were measured by enzymatic

colorimetric assay, using Hitachi cobas C 311. After 12 hours overnight

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fast for all subjects before collection of blood. Low density lipoprotein

cholesterol (LDL –C) was calculated using Friedewald formula (8).

HbA1C : was done by enzymatic colorimetric assay, using Hitchi cobas C

311.

BNP test: BNP samples were taken immediately after exercise testing .The

samples were measured quantitatively by fluorescence immunoassay with the

Alere Triage Meters in EDTA anticoagulated whole blood. ( 9 ) .

4-Resting transthoracic 2- D- doppler Echocardiography

All patients were examined in left lateral position by experienced cardiologist

by using SONO 7500 Philips with 3.5 MHZ probe .

All measurements were done according to the recommendation of American

Society of Echocardiograohy.

Patients with LVH , valvular heart disease and ( EF < 50%) were excluded

from the study .

5-Resting ECG patients with significant abnormalities on resting ECG like:

left bundle branch block ( LBBB) , LV H , atrial fibrillation , ST / T wave

abnormalities , significant bradycardia or tachyarrythmia were excluded .

6-Exercise testing was done by GE Marquette case T 2100 . The test

was performed according to the Bruce protocol. Patients maintained beta

blocker, calcium channel blocker, nitrates was instructed to discontinue these

medications for 48 hours before the test. The procedure is done after 4 hours

fasting. ECG monitoring and heart rate and blood pressure were assessed

before, during exercise and recovery period. The test was terminated

immediately on chest pain, dyspnea

, fatigue, dizziness, appearance of ventricular arrhythmias, marked

tachycardia or bradycardia, significant S-T segments depression ≥3mm .

Stress ECG was interpretated as positive, or normal (10) .

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1- Positive : ≥ 1mm horizontal or downslopin depression of ST segment

after J point .

2-Normal: ST depression < 1mm.

7- Statistical analysis of the obtained results. (11)

Results were statistically analyzed with statistical package for social

science ( SPSS) version 21 .

All data are expressed mean and standard deviation.

Student t- test : for testing statistical significant difference between

mean values of 2 groups by( p-value) as,

P > 0.05 insignificant , P< 0.05 slight significant ,

Chi - Square test : ficto test for statistical significant relation between

different variable and grades in qualitative data .

RESULTS

Fifty (50) diabetic (DM2) normotensive male patients were enrolled in this

study. We excluded patients with history or evidence of heart failure or coronary

artery disease.

A- 36 patients (75%) showed positive exercise testing for myocardial

ischemia (positive Group) their ages ranged from 40 to 59 years and their mean

age was 48.99 9.38.

B- 12 patients (25%) showed normal exercise testing for myocardial ischemia

(normal Group) their ages ranged from 38 to 54 years and their mean age was

434.69 .

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C -2 patients showed equivocal exercise testing results and were excluded from

the Study (not age predicted maximal heart Rate (APMHR).

Table (1): number and percent of positive and normal group. NO %

Positive 36 75

Normal 12 25

Table ( 2): It was found that triglyceride( TG) , total –cholesterol ( TC) ,

LDL –C were significantly higher in positive group patients when

compared to normal group .

Positive Normal Independent t-test

Mean± SD Range Mean± SD Range t P-value

Triglycerides 212.31 42.84 141-288 157.75 48.32 112-269 -3.701 0.001

T-Cholesterol 265.36 41.15 159-336 203.00 55.23 153-317 -4.165 0.000

LDL-C 175.0022.75 110-203 144.33 20.35 90-160 8.200 0.000

HDL-C 60.47 15.94 35-90 45.17 6.65 35-56 3.163 0.003

Comparison between positive group and normal group according to TG , TC ,

LDL – C & HDL – C .

Table ( 3 ): BNP level was found significantly higher in positive group

compared to negative group . (table 3 & figure 1) .

Positive Normal One way ANOVA

Mean± SD Range Mean± SD Range F P-value

BNP Level 43.54 9.63 18.8-68.2 15.43 3.91 4.5-22.3 -9.787 0.000

Comparison between two groups according to BNP level .

Figure ( 1) : comparison between two groups according to BNP level .

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Table (4 ) In positive group patients no significant correlation were found

between BNP level and each of age , duration of diabetes , BMI, WC,

HBA1C, and TG ,Only BNP level was significantly correlated with TC . (

table 4 & Figure 2) .

BNP Level

R P-value

Age (years) 0.229 0.178

Duration of DM (years) -0.107 0.536

HbA1c 0.195 0.255

BMI kg/m2 0.033 0.849

LV EDD/cm -0.028 0.869

EF % 0.256 0.132

Triglycerides mg/dl 0.085 0.620

T-Cholesterol mg/dl 0.286 0.090

-CLDL 0.253 0.071

-CLDH 0.192 0.246

Comparison between BNP and studied parameters in positive groups.

Figure ( 2 ) : Show correlation between BNP level and total cholesterol .

Table (5): IT was found that BNP cut off level > 22.4 pg /ml is sensitive by

88.89 % and specific by 75 % for diagnosis of silent myocardial ischemia.

Cut off point AUC Sensitivity Specificity +PV -PV

>22.4 0.831 88.89 75.00 91.4 69.2

Sensitivity and specificity of BNP in predicting positive Exercise testing in

patients with no history of Ischemic heart disease.

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FIgure ( 3) :Receiver operative characteristic ( ROC) curve describing the ability of

BNP to detect positive exercise testing in Egyptian patients with no history of

ischemic heart disease .

DISCUSSION

There are currently four types of natriuretic peptides that have been

described as ANP , BNP , CNP and DNP . ANP and BNP are primarily released

from the heart. ( 1 ) .

In human, BNP is primarily derived from the ventricular cardiomyocyte . It

has several systemic effects, which counteract CV volume overload including

vasodilatation, diuresis, and inhibition of the Renin – Angiotensin – Aldosterone

system. ( 2 ).

Many studies demonstrated elevated BNP level with more extensive

inducible myocardial ischemia irrespective of LV function. ( 12 ).

BNP was also found to independently predict myocardial ischemia during

dobutamine – stress echocardiography ( 11 ) And correlate well with wall

motion score index and exercise capacity in patients with suspected CAD and

preserved LV function . ( 12) .

BNP may also help to identify CAD In asymptomatic patients and this is

particularly important because patients with silent myocardial ischemia ( SMI )

have a 21 –fold increase risk of coronary event . ( 5) In addition almost 50 % of

sudden cardiac death still occurs in people with no documented previous history

of overt cardiac disease . ( 6 ).

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Diabetic patients have a higher prevalence of SMI and unrecognized

myocardial infarction than patients without diabetes. Patients with diabetes and

SMI have a very poor

Prognosis, as reflected by adverse cardiac events or death.The

prevalence of silent CAD is 6 % to 23 % in low risk diabetic patients. In high

risk diabetic patients, the prevalence may be high as 60 % .So early detection of

silent ischemia is important in diabetics (13 ) .

For this purpose the first necessary step would be able to develop a simple

test which is able to identify those patients with diabetes with silent coronary

artery disease.

This work was planned to screen patients with type 2- DM with BNP (as a

simple test) to identify those with asymptomatic CAD with preserved left

ventricle and suggest cut- off level of BNP that may be appropriate for

myocardial ischemia.

In the present study, 50 normotensive male diabetic ( DM2) patients were

selected from DM outpatient clinic . All had no symptoms of myocardial

ischemia or undergone coronary intervention; also all had normal renal function

and normal echocardiography and all undergone BNP and stress ECG according

to Bruce protocol.

Stress ECG was chosen easily obtainable, low cost and noninvasive, it can be

used as the first diagnostic test for patients with intermediate risk of having

CAD , with fairly sensitivity and specificity .

In the present study, 36 patients ( 75 %) showed positive exercise testing . 12

patients showed normal exercise testing ( normal group )( table 1) . This result

was in agreement with Blandine et al.,& Bacci et al ., (14 )( 15 ) reported

low incidence of abnormal exercise ECG testing (16 %, 19 % respectively )

among asymptomatic T2DM .

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SUPLL - 2

The current study was observed the positive group patients had older age

,longer duration of diabetes , and poor glycemic

control than normal group patients . These results were in accordance with that

concluded by E. Babes et al ., (16) .

In the present study, BNP level was found significantly higher in patients with

positive exercise test than in those with normal exercise tests ( table 3 & figure

1) This was in agreement with Babes et al ., ( 16) & Hamano et al., (18 )&

Cosson et al., (19 ) and Rana et al., (18 ) whose reported that BNP can

identify which asymptomatic patients with type 2 diabetes will have abnormal

exercise test when patients apparent IHD have been excluded . The current

study suggested that BNP level was predict silent myocardial ischemia in

T2DM irrespective of age, duration of DM , BMI ,WC ,glycemic control and

lipid profile except TC . (table 4 & figure 2 ) .and showed that BNP level above

22.4 pg/ml was sensitive by 88.89 % and specific by 75 % in detecting silent

myocardial ischemia in type 2 diabetic patient .(table 5).

Rana et al., ( 17 ) reported that BNP above 20 pg / ml with sensitivity and

specificity for detection of positive exercise test are

87 % and 37% respectively, and BNP value above 35 pg/ml the sensitivity 69 %

and specificity 72 % . and for BNP value above 40 pg /ml sensitivity was 63 %

and specificity 81 % .

CONCLUSION

The study suggested that BNP is a valuable predictor and useful as screening for

silent myocardial ischemia in asymptomatic Egyptian patients with type 2 DM.

RECOMMENDATION

On basis of these data, we hope that future studies on large population are

needed for more evaluation the diagnostic accuracy of serum BNP as an

acceptable substitute of stress ECG for diagnosis of silent myocardial ischemia

and to see different cut off for BNP can perform better in different groups of

patients.

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العربى الملخص

يشض عذ تانجهىد انقهة سعى يع انذس انخ انهشيى عالقح نذساعح انحانيح انذساعح صد

انراجي تانششيا قصىس تحذوز نهرثؤ انثا انىع ي انغكش

انخاسجيح انعيادج ي اخرياسهى ذى وقذ انثا انىع ي انغكشي تانثىل يشيضا50 عهي انذساعح واشرهد

. يعانجا انشعشيح تاب تغرشف نهغكش

. انراج انششيا نقصىس اعشاض اي ي يعاى ال انشض وهؤالء

::الدراسة فى المشاركين لكل االتى عمل تم وقد

وقياط انجغى كرهح يؤشش اخز وذى,انراج انششيا قصىس اعشاض وخاصح انشض انراسيخ اخز ذى

انكىنيغريشول وغة انغكشي انهيىجهثي قياط(انثىنياوانكشياذي)انكه وظائف عم ذى,انخصش يحيط

غثح وقياط تانجهىد, انقهة سعى انقهة, عه انرهيفضيىيح االشعح,انثالثيح وانذهى وانىع انكه

. انذس انخ انهشيى

.( عهثيح ويجىعح ايجاتيح يجىعح)تانجهىد انقهة سعى حغة يجىعري ان انشض ذقغيى ذى

: تىاال عن الدراسة نتائج اسفرت وقد

انخصشتي ويحيط وانجظ كرهح ويؤشش وانىص انشض وفرشج انعش ف احصائيا تها يعرذ صيادج وجذ

.انجىعري

وغة(انغكشي انهيىجهثي) غثح تانذو انغكش اخرالل ف احصائيا تها يعرذ صيادج وجذخ كا

. انثالثيح وانذهى(وانىعي انكه)انكىنيغريشول

انجىعح ف انغكش يشض عذ احصائيح تذالنح يشذفعح كاد انذس انخ انهشيى غثح ا وجذ وقذ

. االيجاتيح

عىايم ي واي انذس انخ انهشيى غثح تي احصائيح دالنح راخ عالقح وجىد انذساعح ذغجم ونى

وغة انغكشي انهيىجهىتي وغثح انخصش ويحيط انعش يثم انذيىيح واالوعيح انقهة عه انخطىسج

.. انكه انكىنيغريشول غثح يع ايجاتيح عالقح وجىد فقط/ انذهى

ف اكثش حغاعيح ذثم يم/تيكىجشاو 22.4 ي اكثش انذس انخ انهشيى غثح صيادج ا وجذ وقذ

.انثا انىع ي انغكش يشضي عذ انقصىس ذشخيص

يشض ف انراج تانششيا قصىس تىجىد يرثئ انذس انخ انهشيى ا ان انذساعح خهصد وقذ

انذقح دسجاخ اعه ذثم يم/تكىجشاو 22.4 ي اكثش تغثح انضيادج وا انثا انىع ي انغكشي انثىل

.انرشخيصيح

انذقح وذقيى احصاء ذغرطيع اتحاثا ذشجع يغرقثهيح دساعاخ تعم انذساعح ذىص هزا ضىء وف

قصىس وذشخيص انرثؤ ف تانجهىد انقهة سعى ع يقثىل كثذيم انذس انخ نههشيى انرشخيصيح

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B-TYPE NATRIURETIC PEPTIDE (PNP) CAN PREDICT SILENT