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Predictors of Ischaemia and Outcomes in Egyptian Patients with Diabetes
Mellitus Referred for Perfusion Imaging
Samir Rafla*, Ahmed Abdel-Aaty, Mohamed Ahmed Sadaka, Aly Ahmed Abo Elhoda and Ahmed Mohamed Shams
Department of Cardiology and Angiology, Faculty of Medicine, Alexandria University, Egypt
*Corresponding author: Samir Rafla, Faculty of Medicine, Alexandria University, 398 Tareek Elhoria, 21321, Egypt, Tel: +201001495577; Fax: 00201001495577; E-
mail: smrafla@yahoo.com
Received date: May 17, 2018; Accepted date: June 13, 2018; Published date: June 21, 2018
Copyright: ©2018 Rafla S, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use,
distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
The predictors of scintigraphic ischemia were studied in 169 Egyptian diabetic patients. They underwent stress-
rest gated-SPECT myocardial perfusion imaging (MPI) protocol; also 25 subjects (control group) underwent Rest-
Redistribution MPI protocol. The patients were followed up to 24 months.
Results: We found significant relation between Summed stress score (SSS) and sudden cardiac death, MI and
HF. Also there were statistically significant relation between atypical pain and HF. We found significant relation
between summed rest scores (SRS) and sudden cardiac death, MI, HF, and stroke with p<0.001, p<0.038, p<0.001
and p<0.016 respectively. On applying univariate, multivariate analysis and Kaplan Meier survival for prognostic
variables for MI, we found degree of typical pain (CCS class) is the most prognostic with HR=6.100, followed by TID
of LV, lung uptake and SSS with HR=1.401, HR=1.115, and HR=1.100 respectively. Also we found that transient
ischemic dilation (TID) of LV is the most prognostic variable for sudden cardiac death with HR=5.077, followed by
SSS, SRS, degree of pain (Canadian Cardiovascular Society classification of chest pain (CCS) class), with
HR=2.682, HR=2.636, HR=2.008, respectively.
Conclusion: Semi-quantitative parameters such as SSS, SRS, SDS and percentage of ischaemic myocardium
are independent predictors of MACE in both symptomatic and asymptomatic diabetic Egyptian patients, also In our
cohort of diabetic patients we found high ischaemic burden, 39.2% of patients who had >10% ischaemic
myocardium.
Keywords: Thallium-201; Diabetes; Coronary artery disease; SPECT;
Prognosis
Introduction
Diabetes mellitus has emerged as a significant health problem with
international importance [1].
Cardiovascular diseases account for between 70% and 80% of the
mortality in diabetic patients [2,3]. In a series of 4755 patients
presenting with suspected CAD undergoing MPI investigation, even in
a relatively short follow up period of 2.5 years, the diabetic cohort
sustained nearly twice (8.6% vs. 4.5%) the cardiac event rate (cardiac
death or nonfatal MI) compared to the non-diabetic patients
(p<0.0001) [4].
Myocardial perfusion imaging (MPI) with single photon emission
computed tomography (SPECT) has been extensively employed as a
diagnostic tool in CAD, and is a potent prognostic tool for risk
stratification [4-8]. Indeed, its role in diabetic patients with
asymptomatic CAD has been widely reported [9]. MPI plays an
important role in identifying those diabetic patients most at risk of
CAD and, thus, in need of more aggressive management [9]. This is
important because once CAD is symptomatic, diabetic patients
confront significant morbidity and risk of mortality [9]. A number of
investigators have examined the role of MPI in detection of silent
ischemia among diabetic patients with no known or suspected CAD.
In an asymptomatic population, Mohagheghie et al. [9] reported 30.1%
of patients to have an abnormal MPI; most (92%) with reversible
defects. Prior et al. [7] reported a 31% prevalence of silent ischemia in
diabetic patients.
The aim was to estimate the prevalence and to detect the predictors
of significant scintigraphic ischemia and subsequent cardiac events in a
cohort of stable outpatients with DM referred for SPECT MPI. Also to
assess the impact of gender, comorbidities, type of stress, and symptom
status on these findings.
This study was conducted to examine the incremental prognostic
value of SPECT MPI in risk stratification of an Egyptian diabetic
patient population with known or suspected CAD.
Methods
Study population
The study population was a consecutive cohort of patients with
suspected CAD or known CAD referred for diagnostic investigation
with SPECT-MPI at the Alexandria Main University hospital Gama
camera unit. The study was conducted on 194 diabetic patients who
were referred to undergo SPECT stress MPI in cardiology nuclear
laboratory in Alexandria Main University Hospital retrospectively
during the period from 1-1-2012 to 1-1-2016; as well as the prospective
cases during the period from 1-4-2016 to 1-7-2016.
Inclusion criteria: All patients with DM referred to do SPECT-MPI.
J
ournalofClini
cal & Experime
ntalCardiology
ISSN: 2155-9880
Journal of Clinical and Experimental
Cardiology Rafla et al., J Clin Exp Cardiolog 2018, 9:6
DOI: 10.4172/2155-9880.1000591
Research Article Open Access
J Clin Exp Cardiolog, an open access journal
ISSN:2155-9880
Volume 9 • Issue 6 • 1000591
Exclusion criteria: 1. Patients with CCS IV anginal pain. 2. Patients
with electrical or hemodynamic unstability.
SPECT-MPI Study
One hundred sixty nine subjects underwent stress-rest gated-
SPECT MPI protocol; also 25 subjects underwent Rest-Redistribution
Protocol SPECT-MPI was performed. Supine images were acquired
with a dual-head symbia E Siemens Gama camera with low-energy and
high-resolution collimators. Each camera head acquired 180°C of data
by 60 projections at 30 to 40 seconds per projections. The data from
the 2 heads were combined to give 360°C of coverage.
Radionuclide Image Processing
All radionuclide images and associated data were processed
according to standard protocols using proprietary V-Quant software
(Charlottesville, VA). Myocardial perfusion was calculated as the
relative percent tracer uptake in each of the 17 segments of a standard
model) Uptake deviating ≥ 2 SDs from institution-derived sex-specific
normal databases was flagged as abnormal in a reversible or fixed
pattern [10,11]. Experienced nuclear cardiology specialists used this
quantitative data as well as visual image analysis to interpret each MPI
study [12-15]. Readers assigned a score to each segment (0-4 for
normal, mild, moderate, severe, and absent uptake, respectively). The
semi-quantitative summed stress, rest, and difference scores were
calculated from these segmental values, with the 5 apical segments
receiving 40% weighting (each apical segmental score × 0.4) to correct
for the over-representation of the apex partially in the standard 17-
segment model. Finally, the percentage of myocardial ischemia was
obtained by dividing the difference between summed stress and
summed rest scores by 56, the maximum possible difference. LV
ischemia of 1% to 9% was considered mild-moderate, and ≥ 10% LV
ischemia was considered significant. Non-Perfusion Parameters:
transient ischemic dilation (TID) of LV and lung uptake was recorded.
Lung uptake: A qualitative assessment of lung 201TI uptake was
made by two observers for each image. A grade of 0 was chosen for
qualitatively normal pulmonary uptake, 1+ for moderately increased
pulmonary uptake that was greater than normal but less than
myocardial activity, and 2+ for greatly increased pulmonary activity
that approached myocardial activity. Half grades were allowed. The
grades of the two observers were averaged for each observation.
Follow-up: Data of cardiac mortality, nonfatal MI, decompensated
HF, stroke and revascularization were collected initially through ≥ 3
follow-up telephone contact attempts, follow up was done to 135
patients for two years, to six patients for one year and not available to
53 patients.
Clinical Characteristics at Baseline and Follow-up
Clinical characteristics were obtained at baseline and at follow-up
visits. Traditional risk factors such as diabetes, hypertension, and
dyslipidemia, smoking and family history of premature CAD were also
established. Diabetes mellitus was defined according to American
Diabetes Association criteria and was considered present if the patient
used oral diabetic medications or insulin.
Statistical analysis of the data [16]
All continuous variables are expressed as the mean value ± SD. The
mean differences for continuous variables were compared by the
Student t test (2-tailed). Categorical variables were compared as means
using a χ2 (chi square) statistic. A P value <0.05 was considered
statistically significant. The Kaplan Meier survival curve was used
(Table 1).
Variable Description (%)
Age (years) 58.79 ± 9.52
Gender
Male 131 (67.5)
Risk factors
HTN 131(67.5)
IDDM 26 (13.4)
DM type 2 168 (86.6)
Dyslipidemia 48 (24.7)
Family history 76 (39.2)
Smoking 124 (63.9)
Abnormal SPECT-MPI
SSS (>8) 137 (70.6)
SRS (>8) 99 (51.0%)
Transient LV dilation 120 (61.9)
Lung uptake 73 (37.6)
Percentage of ischemia ≥ 10 76 (39.2)
Symptom
Typical CCS 179 (92)
Atypical 15 (7.7)
Follow Up
Sudden Cardiac death 35 (18.0)
MI 44 (22.7)
HF 73 (37.6)
Stroke 18 (9.3)
Not Available 53 (27.3)
Revascularization
Table 1: Base Line Characteristics of the Study population
Results
There was statistically significant relation between CCS class and MI
(p<0.001). There was statistically significant relation between CCS
class and HF (p=0.002) (Figure 1).
Citation: Rafla S, Abdel-Aaty A, Sadaka MA, Elhoda AAA, Shams AM (2018) Predictors of Ischaemia and Outcomes in Egyptian Patients with
Diabetes Mellitus Referred for Perfusion Imaging . J Clin Exp Cardiolog 9: 591. doi:10.4172/2155-9880.1000591
Page 2 of 6
J Clin Exp Cardiolog, an open access journal
ISSN:2155-9880
Volume 9 • Issue 6 • 1000591
Figure 1: Relation between degree of angina pain and outcome.
There was no statistically significant relation between age and SSS
(P=0.549) There was statistically significant relation between male
gender and (P=0.04) (Table 2,3). There was statistically significant
relation between IDDM and SSS (P=0.028). There was statistically
significant relation between DM type 2 and SSS (P=0.029). There was
statistically significant relation between HTN and SSS (P=0.030).
SSS Outcomes P
0-3
(n=26)
4-8
(n=31)
>8
(n=137)
No. % No. % No. %
Demographic data Age (years) 2.822 MCp=0.549
<40 1 3.8 1 3.2 3 2.2
40-60 15 57.7 20 64.5 72 52.6
>60 10 38.5 10 32.3 62 45.3
Gender 6.450* 0.040*
Male 12 46.2 23 74.2 96 70.1
Female 14 53.8 8 25.8 41 29.9
Risk factors IDDM 3 11.5 9 29.0 14 10.2 6.817* MCp=0.028*
NIDDM 23 88.5 22 71.0 123 89.8 6.817* MCp=0.029*
HTN 12 46.2 20 64.5 99 72.3 6.817* 0.030*
Dyslipidemia 5 19.2 8 25.8 35 25.5 0.491 0.782
Smoking 10 38.5 22 71.0 92 67.2 8.595* 0.014*
Family history 10 38.5 15 48.4 51 37.2 1.328 0.515
Follow up Sudden Cardiac death 1 3.8 0 0.0 34 24.8 14.621* 0.001*
MI 0 0.0 9 29.0 35 25.5 8.982* 0.002*
HF 3 11.5 6 19.4 64 46.7 16.771* <0.001*
Stroke 0 0.0 2 6.5 16 11.7 3.597 MCp=0.174
Table 2: Relation between demographic data, risk factors, outcomes and SSS
SRS Outcome
s
p
0-3
(n=57)
4-8
(n=38)
>8
(n=99)
No
.
% No
.
% No
.
%
Age (years)
<40 3 5.3 0 0.0 2 2.0
6.544
MCp=0.12
7
Citation: Rafla S, Abdel-Aaty A, Sadaka MA, Elhoda AAA, Shams AM (2018) Predictors of Ischaemia and Outcomes in Egyptian Patients with
Diabetes Mellitus Referred for Perfusion Imaging . J Clin Exp Cardiolog 9: 591. doi:10.4172/2155-9880.1000591
Page 3 of 6
J Clin Exp Cardiolog, an open access journal
ISSN:2155-9880
Volume 9 • Issue 6 • 1000591
40-60 37
64.
9
20
52.
6
50
50.
5
>60 17
29.
8
18
47.
4
47
47.
5
Ri
sk
fa
ct
or
s
IDDM 10
17.
5
3 7.9 13
13.
1
1.842 0.398
NIDDM 47
82.
5
35
92.
1
86
86.
9
1.842 0.398
HTN 33
57.
9
27
71.
1
71
71.
1 3.337 0.187
Dyslipidemia 12
21.
1
7
18.
4
29
29.
3
2.333 0.311
Smoking 27
47.
4
19
50.
0
78
78.
8 19.452* <0.001*
Family
history
28
49.
1
14
36.
8
34
34.
3
3.424 0.181
Fo
llo
w
up
Sudden
Cardiac
death
3 5.3 1 2.6 31
31.
3
24.190* <0.001*
MI 7
12.
3
13
34.
2
24
24.
2
6.630* 0.038*
HF 12
21.
1
8
21.
1
53
53.
5
21.795* <0.001*
Stroke 2 3.5 1 2.6 15
15.
2
8.306* 0.016*
Table 3: Relation between SRS, demographic data, risk factors and
clinical outcomes
There was statistically significant relation between smoking and SSS
(P=0.014) There were statistically significant relation between sudden
cardiac death, MI, HF and SSS P=0.001, P=0.002, and P<0.001
respectively, Figure 2.
Figure 2: Relation between Summed stress score (SSS) and follow
up.
There were statistically significant relation between SRS, sudden
cardiac death, MI, HF, and stroke with p<0.001, p=0.038, p<0.001
p=0.016 respectively.
Correlation analysis was performed utilizing degree of complaint
(CCS class), sudden cardiac death, MI and HF, We found that there
was positive correlation between CCS class of anginal pain and sudden
cardiac death (r=0.166, p=0.026).There was a positive correlation
between CCS class of angina pain and MI (r=0.282, p<0.001) There
was positive correlation between CCS class of angina pain and HF
(r=0.251, p=0.001).
Correlation analysis was performed utilizing SRS, sudden cardiac
death, MI, HF, and stroke. We found: There was positive correlation
between SRS and sudden cardiac death (r=0.344, p<0.001). There was
no correlation between SRS and MI. (r=0.121, p=0.094). There was
strong positive correlation SRS and HF. (r=0.333, p<0.001) There was
positive correlation between stroke and SRS (r=0.200, p=0.005).
Also we found There was strong positive correlation between SSS
and sudden cardiac death (r=0.396, p<0.001), There was positive
correlation between SSS and MI (r=0.142, p=0.049), There is strong
positive correlation between SSS and HF (r=0.370, p<0.001); and There
was positive correlation between SSS and stroke (r=0.233, p=0.001),
Table 3.
Univariate and Multivariate Analysis for Variables
Associated with MI
We found that, typical pain is the most predictive variable for MI
(p=0.001, HR=6.100), also, SSS, lung uptake, transient LV dilation, all
of them have a predictive value for MI with HR=1.100, 1.115, and
1.401 respectively. On multivariate analysis typical pain is the most
predictive (p=0.001 HR=6.100), Tables 4,5.
p HR
95% CI
LL UL
SSS (>8) 0.021* 2.587* 1.151 5.815
Lung uptake 0.046* 1.845* 1.012 3.363
Transient LV dilation 0.039* 1.959* 1.034 3.712
Typical pain <0.001* 0.151* 0.054 0.423
Table 4: Univariate analysis for variables prognostic for MI.
On univariate analysis, we found that the following variables were
predictors of sudden cardiac death; SSS (p=0.006, HR=15.901), TID of
LV (P<0.001, HR=14.492), SRS (P<0.001, HR=10.321), lung uptake
(P<0.001, HR=5.844), typical angina pain (P=0.012, HR=3.121) and
age (P=0.024, HR=2.217). But on multivariate analysis TID of LV was
the most predictor (P=0.041, HR=5.077).
p HR
95% CI
LL UL
Age (≥ 60) 0.024* 2.174* 1.106 4.276
SSS (>8) 0.006* 15.901* 2.175 116.26
SRS (>8) <0.001* 10.321* 3.636 29.30
Lung uptake <0.001* 5.844* 2.795 12.200
Transient LV dilation <0.001* 14.492* 3.468 60.547
Citation: Rafla S, Abdel-Aaty A, Sadaka MA, Elhoda AAA, Shams AM (2018) Predictors of Ischaemia and Outcomes in Egyptian Patients with
Diabetes Mellitus Referred for Perfusion Imaging . J Clin Exp Cardiolog 9: 591. doi:10.4172/2155-9880.1000591
Page 4 of 6
J Clin Exp Cardiolog, an open access journal
ISSN:2155-9880
Volume 9 • Issue 6 • 1000591
Typical pain 0.012* 3.121* 1.289 7.558
Table 5: Univariate analysis for variables prognostic for Sudden
Cardiac death.
Discussion
One of the strengths of nuclear MPI is the abundance of the
published literature addressing its prognostic implications, Klocke et
al., Iskandrian et al., Bourque et al., and Di Carli et al. demonstrated
that MPI is most frequently performed using the nuclear techniques of
SPECT and positron emission tomography (PET). When first
introduced half a century ago, SPECT and PET were primarily viewed
as diagnostic tools. Beginning with the publication of a landmark
paper by Brown in 1991, the major role of MPI has shifted from simply
detecting CAD to providing relevant prognostic information and
aiding in risk stratification and management decisions [17-21].
Prognostic relevance of symptoms versus objective evidence
of coronary artery disease in diabetic patients
In our study, typical anginal pain and also atypical angina pain both
of them were associated with significant scintigraphic parameters,
there is statistically significant relation between atypical pain in
diabetics and SSS (P=0.001), also there is statistically significant
relation between atypical pain in diabetics and SRS. (X=10.491,
P=0.004), and there is statistically significant relation between atypical
pain and SDS (P=0.018). We found that there was positive correlation
between CCS class of anginal pain and sudden cardiac death (r=0.166,
p=0.026).
There was strong positive correlation between CCS class of angina
pain and MI (r=0.282, p<0.001).
In Zellweger et al. study of a large, consecutive series of diabetic
patients referred for evaluation of possible or suspected CAD showed
that silent CAD, as diagnosed by MPS, was found in 39% of patients.
The rate of abnormal MPS results did not differ from that of patients
with angina or angina like chest pain, in contrast to non-diabetic
patients [17]. In our study and in previous studies there is strong
correlation between the symptoms and hard and soft cardiac events,
but in our study those who had atypical are statistically related only to
HF, and this may absence of awareness about atypical presentation of
CAD in diabetics, so unfortunately the patients present with heart
failure due to misdiagnosis of MI.
Prognostic yield of semiquantitative parameters in diabetic
patients
In our study, we categorize SSS and SRS as normal SSS 0 to 3; mild
SSS 4 to 8; and moderate to severe abnormal SSS>9. And this similar to
what was done by Kasim et al. [18].
In our study we apply the semiquantitative role, and we found that
there is statistically significant relation between SSS and soft and hard
cardiac events, as regard sudden cardiac death (X=14.621, p=0.001),
also there was statistically significant relation between SSS and MI
(X=8.982, p=0.002), more over the most significant relation was
between SSS and HF (X=16.771, p<0.001).
Also, in our study, there were statistically significant relations
between SRS and MI (X=6.630, p=0.038), statistically significant
relation between SRS and stroke (X=8.306, p=0.016). Moreover, we
found statistically significant relation between SRS and HF (X=21.795,
p<0.001).
Also we found statistically significant relation between SRS and
sudden cardiac death (X=24.190, p<0.001).
On applying correlation analysis between SSS and outcomes, we
found significant positive correlation between SSS and MI (r=0.142
p=0.049), stroke (r=0.233, p=0.001), but the most significant positive
correlation was between SSS and sudden cardiac death (r=0.396,
p<0.001) followed by HF (r=0.370, p<0.001).
On correlation analysis between SRS and outcomes, we found that
the most significant positive correlation with sudden cardiac death
(r=0.344, p<0.001), followed by HF (R=0.333, p<0.001). Also there was
significant positive correlation between SRS and MI (r=0.333, p=0.094)
also positive correlation with stroke (r=0.200, p=0.005).
So in our study SSS and SRS, both of them have positive correlation
with hard and soft cardiac events especially sudden cardiac death and
heart HF.
In our study on applying Kaplan Meier survival curve, we found
that SSS is a predictor sudden cardiac death (HR=2.682). Also SRS can
predict sudden cardiac death (HR=2.66), HF (HR=1.298), and stroke
(HR=1.281). This is more severe in our study, when the SSS >8, the rate
of sudden cardiac death is 24.8%, and rate of MI is 25.5% but the rate
of HF is 47%.
Although SSS is the MPI variable that has been most extensively
validated for prognosis, SDS may be the best predictor of nonfatal
myocardial infarction and is the variable most predictive of subsequent
coronary angiography and early revascularization [22,23].
In our study SDS ranged from 0 to 24.0 with mean ± SD=5.23 ±
4.77. Hachamovitch et al. demonstrated that SDS can be calculated as
the percent myocardium ischemic by dividing SDS by 68 (17 segments
with a maximal score of 4 per segment) × 100. Using the 17 segment
model, a SDS score of 7 is equivalent to 10% of the myocardium
ischemic. In his study this threshold was demonstrated to represent the
amount of ischemic myocardium necessary to demonstrate an
improvement in outcome in patients treated by revascularization vs.
those treated with medications alone [24].
Transient ischaemic dilation of LV
Petretta et al. demonstrated that TID of LV provides additional
value over clinical and perfusion data to identify the presence of severe
CAD in diabetic patients. When abnormal TID was considered in
addition to summed stress score the sensitivity for diagnosing the
diabetic patients with severe CAD improved without reducing
specificity. TID of LV was used to reclassify patients with borderline
perfusion defects (summed stress score between 3 and 7) [23]. In our
study of 194 diabetic patients, TID of LV was present in 120 patients
(61.9%), there was statistically significant relation between TID of LV
and dyspnea (X=23.020, p<0.001).
On applying Multivariate analysis for parameters associated with
HF, TID of LV was the most predictive factor (P<0.001 HR=4.329).
Lung thallium uptake
On applying univariate, multivariate analysis and Kaplan Meier
curve, we found that lung uptake was prognostic to MI, sudden cardiac
death, HF, and stroke (HR=1.115, HR=1.552, HR=1.208, and
Citation: Rafla S, Abdel-Aaty A, Sadaka MA, Elhoda AAA, Shams AM (2018) Predictors of Ischaemia and Outcomes in Egyptian Patients with
Diabetes Mellitus Referred for Perfusion Imaging . J Clin Exp Cardiolog 9: 591. doi:10.4172/2155-9880.1000591
Page 5 of 6
J Clin Exp Cardiolog, an open access journal
ISSN:2155-9880
Volume 9 • Issue 6 • 1000591
HR=2.576 respectively), these results are in harmony with the previous
studies of Iskandrian et al. [25].
We found that TID of LV was strongly prognostic to sudden cardiac
death (P=0.041, HR=5.077), and, TID of LV had a prognostic value to
MI (HR=1.401). Also it had prognostic value to stroke (HR=9.967).
Study limitations
1. This is a single center study.
2. This is an observational study.
3. No available registry data about the duration of DM and the
degree of glycemic control.
4. Follow up data was not available in 53 patients, i.e. about 27%.
However, the results through light on predictors of MACE in
Egyptian diabetic patients.
Conclusion
Semi-quantitative parameters such as SSS, SRS, SDS and percentage
of ischaemic myocardium are independent predictors of MACE in
both symptomatic and asymptomatic diabetic patients, also non-
perfusion parameters such as TID of LV and lung uptake were found to
have strong prognostic yield in diabetic patients.
In our cohort of diabetic Egyptian patients we found high ischaemic
burden in (39.2% of patients had >10% ischaemic myocardium).
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Citation: Rafla S, Abdel-Aaty A, Sadaka MA, Elhoda AAA, Shams AM (2018) Predictors of Ischaemia and Outcomes in Egyptian Patients with
Diabetes Mellitus Referred for Perfusion Imaging . J Clin Exp Cardiolog 9: 591. doi:10.4172/2155-9880.1000591
Page 6 of 6
J Clin Exp Cardiolog, an open access journal
ISSN:2155-9880
Volume 9 • Issue 6 • 1000591

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J clin exp card predictors of ischaemia and outcomes in egyptian patients with diabetes

  • 1. Predictors of Ischaemia and Outcomes in Egyptian Patients with Diabetes Mellitus Referred for Perfusion Imaging Samir Rafla*, Ahmed Abdel-Aaty, Mohamed Ahmed Sadaka, Aly Ahmed Abo Elhoda and Ahmed Mohamed Shams Department of Cardiology and Angiology, Faculty of Medicine, Alexandria University, Egypt *Corresponding author: Samir Rafla, Faculty of Medicine, Alexandria University, 398 Tareek Elhoria, 21321, Egypt, Tel: +201001495577; Fax: 00201001495577; E- mail: smrafla@yahoo.com Received date: May 17, 2018; Accepted date: June 13, 2018; Published date: June 21, 2018 Copyright: ©2018 Rafla S, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Abstract The predictors of scintigraphic ischemia were studied in 169 Egyptian diabetic patients. They underwent stress- rest gated-SPECT myocardial perfusion imaging (MPI) protocol; also 25 subjects (control group) underwent Rest- Redistribution MPI protocol. The patients were followed up to 24 months. Results: We found significant relation between Summed stress score (SSS) and sudden cardiac death, MI and HF. Also there were statistically significant relation between atypical pain and HF. We found significant relation between summed rest scores (SRS) and sudden cardiac death, MI, HF, and stroke with p<0.001, p<0.038, p<0.001 and p<0.016 respectively. On applying univariate, multivariate analysis and Kaplan Meier survival for prognostic variables for MI, we found degree of typical pain (CCS class) is the most prognostic with HR=6.100, followed by TID of LV, lung uptake and SSS with HR=1.401, HR=1.115, and HR=1.100 respectively. Also we found that transient ischemic dilation (TID) of LV is the most prognostic variable for sudden cardiac death with HR=5.077, followed by SSS, SRS, degree of pain (Canadian Cardiovascular Society classification of chest pain (CCS) class), with HR=2.682, HR=2.636, HR=2.008, respectively. Conclusion: Semi-quantitative parameters such as SSS, SRS, SDS and percentage of ischaemic myocardium are independent predictors of MACE in both symptomatic and asymptomatic diabetic Egyptian patients, also In our cohort of diabetic patients we found high ischaemic burden, 39.2% of patients who had >10% ischaemic myocardium. Keywords: Thallium-201; Diabetes; Coronary artery disease; SPECT; Prognosis Introduction Diabetes mellitus has emerged as a significant health problem with international importance [1]. Cardiovascular diseases account for between 70% and 80% of the mortality in diabetic patients [2,3]. In a series of 4755 patients presenting with suspected CAD undergoing MPI investigation, even in a relatively short follow up period of 2.5 years, the diabetic cohort sustained nearly twice (8.6% vs. 4.5%) the cardiac event rate (cardiac death or nonfatal MI) compared to the non-diabetic patients (p<0.0001) [4]. Myocardial perfusion imaging (MPI) with single photon emission computed tomography (SPECT) has been extensively employed as a diagnostic tool in CAD, and is a potent prognostic tool for risk stratification [4-8]. Indeed, its role in diabetic patients with asymptomatic CAD has been widely reported [9]. MPI plays an important role in identifying those diabetic patients most at risk of CAD and, thus, in need of more aggressive management [9]. This is important because once CAD is symptomatic, diabetic patients confront significant morbidity and risk of mortality [9]. A number of investigators have examined the role of MPI in detection of silent ischemia among diabetic patients with no known or suspected CAD. In an asymptomatic population, Mohagheghie et al. [9] reported 30.1% of patients to have an abnormal MPI; most (92%) with reversible defects. Prior et al. [7] reported a 31% prevalence of silent ischemia in diabetic patients. The aim was to estimate the prevalence and to detect the predictors of significant scintigraphic ischemia and subsequent cardiac events in a cohort of stable outpatients with DM referred for SPECT MPI. Also to assess the impact of gender, comorbidities, type of stress, and symptom status on these findings. This study was conducted to examine the incremental prognostic value of SPECT MPI in risk stratification of an Egyptian diabetic patient population with known or suspected CAD. Methods Study population The study population was a consecutive cohort of patients with suspected CAD or known CAD referred for diagnostic investigation with SPECT-MPI at the Alexandria Main University hospital Gama camera unit. The study was conducted on 194 diabetic patients who were referred to undergo SPECT stress MPI in cardiology nuclear laboratory in Alexandria Main University Hospital retrospectively during the period from 1-1-2012 to 1-1-2016; as well as the prospective cases during the period from 1-4-2016 to 1-7-2016. Inclusion criteria: All patients with DM referred to do SPECT-MPI. J ournalofClini cal & Experime ntalCardiology ISSN: 2155-9880 Journal of Clinical and Experimental Cardiology Rafla et al., J Clin Exp Cardiolog 2018, 9:6 DOI: 10.4172/2155-9880.1000591 Research Article Open Access J Clin Exp Cardiolog, an open access journal ISSN:2155-9880 Volume 9 • Issue 6 • 1000591
  • 2. Exclusion criteria: 1. Patients with CCS IV anginal pain. 2. Patients with electrical or hemodynamic unstability. SPECT-MPI Study One hundred sixty nine subjects underwent stress-rest gated- SPECT MPI protocol; also 25 subjects underwent Rest-Redistribution Protocol SPECT-MPI was performed. Supine images were acquired with a dual-head symbia E Siemens Gama camera with low-energy and high-resolution collimators. Each camera head acquired 180°C of data by 60 projections at 30 to 40 seconds per projections. The data from the 2 heads were combined to give 360°C of coverage. Radionuclide Image Processing All radionuclide images and associated data were processed according to standard protocols using proprietary V-Quant software (Charlottesville, VA). Myocardial perfusion was calculated as the relative percent tracer uptake in each of the 17 segments of a standard model) Uptake deviating ≥ 2 SDs from institution-derived sex-specific normal databases was flagged as abnormal in a reversible or fixed pattern [10,11]. Experienced nuclear cardiology specialists used this quantitative data as well as visual image analysis to interpret each MPI study [12-15]. Readers assigned a score to each segment (0-4 for normal, mild, moderate, severe, and absent uptake, respectively). The semi-quantitative summed stress, rest, and difference scores were calculated from these segmental values, with the 5 apical segments receiving 40% weighting (each apical segmental score × 0.4) to correct for the over-representation of the apex partially in the standard 17- segment model. Finally, the percentage of myocardial ischemia was obtained by dividing the difference between summed stress and summed rest scores by 56, the maximum possible difference. LV ischemia of 1% to 9% was considered mild-moderate, and ≥ 10% LV ischemia was considered significant. Non-Perfusion Parameters: transient ischemic dilation (TID) of LV and lung uptake was recorded. Lung uptake: A qualitative assessment of lung 201TI uptake was made by two observers for each image. A grade of 0 was chosen for qualitatively normal pulmonary uptake, 1+ for moderately increased pulmonary uptake that was greater than normal but less than myocardial activity, and 2+ for greatly increased pulmonary activity that approached myocardial activity. Half grades were allowed. The grades of the two observers were averaged for each observation. Follow-up: Data of cardiac mortality, nonfatal MI, decompensated HF, stroke and revascularization were collected initially through ≥ 3 follow-up telephone contact attempts, follow up was done to 135 patients for two years, to six patients for one year and not available to 53 patients. Clinical Characteristics at Baseline and Follow-up Clinical characteristics were obtained at baseline and at follow-up visits. Traditional risk factors such as diabetes, hypertension, and dyslipidemia, smoking and family history of premature CAD were also established. Diabetes mellitus was defined according to American Diabetes Association criteria and was considered present if the patient used oral diabetic medications or insulin. Statistical analysis of the data [16] All continuous variables are expressed as the mean value ± SD. The mean differences for continuous variables were compared by the Student t test (2-tailed). Categorical variables were compared as means using a χ2 (chi square) statistic. A P value <0.05 was considered statistically significant. The Kaplan Meier survival curve was used (Table 1). Variable Description (%) Age (years) 58.79 ± 9.52 Gender Male 131 (67.5) Risk factors HTN 131(67.5) IDDM 26 (13.4) DM type 2 168 (86.6) Dyslipidemia 48 (24.7) Family history 76 (39.2) Smoking 124 (63.9) Abnormal SPECT-MPI SSS (>8) 137 (70.6) SRS (>8) 99 (51.0%) Transient LV dilation 120 (61.9) Lung uptake 73 (37.6) Percentage of ischemia ≥ 10 76 (39.2) Symptom Typical CCS 179 (92) Atypical 15 (7.7) Follow Up Sudden Cardiac death 35 (18.0) MI 44 (22.7) HF 73 (37.6) Stroke 18 (9.3) Not Available 53 (27.3) Revascularization Table 1: Base Line Characteristics of the Study population Results There was statistically significant relation between CCS class and MI (p<0.001). There was statistically significant relation between CCS class and HF (p=0.002) (Figure 1). Citation: Rafla S, Abdel-Aaty A, Sadaka MA, Elhoda AAA, Shams AM (2018) Predictors of Ischaemia and Outcomes in Egyptian Patients with Diabetes Mellitus Referred for Perfusion Imaging . J Clin Exp Cardiolog 9: 591. doi:10.4172/2155-9880.1000591 Page 2 of 6 J Clin Exp Cardiolog, an open access journal ISSN:2155-9880 Volume 9 • Issue 6 • 1000591
  • 3. Figure 1: Relation between degree of angina pain and outcome. There was no statistically significant relation between age and SSS (P=0.549) There was statistically significant relation between male gender and (P=0.04) (Table 2,3). There was statistically significant relation between IDDM and SSS (P=0.028). There was statistically significant relation between DM type 2 and SSS (P=0.029). There was statistically significant relation between HTN and SSS (P=0.030). SSS Outcomes P 0-3 (n=26) 4-8 (n=31) >8 (n=137) No. % No. % No. % Demographic data Age (years) 2.822 MCp=0.549 <40 1 3.8 1 3.2 3 2.2 40-60 15 57.7 20 64.5 72 52.6 >60 10 38.5 10 32.3 62 45.3 Gender 6.450* 0.040* Male 12 46.2 23 74.2 96 70.1 Female 14 53.8 8 25.8 41 29.9 Risk factors IDDM 3 11.5 9 29.0 14 10.2 6.817* MCp=0.028* NIDDM 23 88.5 22 71.0 123 89.8 6.817* MCp=0.029* HTN 12 46.2 20 64.5 99 72.3 6.817* 0.030* Dyslipidemia 5 19.2 8 25.8 35 25.5 0.491 0.782 Smoking 10 38.5 22 71.0 92 67.2 8.595* 0.014* Family history 10 38.5 15 48.4 51 37.2 1.328 0.515 Follow up Sudden Cardiac death 1 3.8 0 0.0 34 24.8 14.621* 0.001* MI 0 0.0 9 29.0 35 25.5 8.982* 0.002* HF 3 11.5 6 19.4 64 46.7 16.771* <0.001* Stroke 0 0.0 2 6.5 16 11.7 3.597 MCp=0.174 Table 2: Relation between demographic data, risk factors, outcomes and SSS SRS Outcome s p 0-3 (n=57) 4-8 (n=38) >8 (n=99) No . % No . % No . % Age (years) <40 3 5.3 0 0.0 2 2.0 6.544 MCp=0.12 7 Citation: Rafla S, Abdel-Aaty A, Sadaka MA, Elhoda AAA, Shams AM (2018) Predictors of Ischaemia and Outcomes in Egyptian Patients with Diabetes Mellitus Referred for Perfusion Imaging . J Clin Exp Cardiolog 9: 591. doi:10.4172/2155-9880.1000591 Page 3 of 6 J Clin Exp Cardiolog, an open access journal ISSN:2155-9880 Volume 9 • Issue 6 • 1000591
  • 4. 40-60 37 64. 9 20 52. 6 50 50. 5 >60 17 29. 8 18 47. 4 47 47. 5 Ri sk fa ct or s IDDM 10 17. 5 3 7.9 13 13. 1 1.842 0.398 NIDDM 47 82. 5 35 92. 1 86 86. 9 1.842 0.398 HTN 33 57. 9 27 71. 1 71 71. 1 3.337 0.187 Dyslipidemia 12 21. 1 7 18. 4 29 29. 3 2.333 0.311 Smoking 27 47. 4 19 50. 0 78 78. 8 19.452* <0.001* Family history 28 49. 1 14 36. 8 34 34. 3 3.424 0.181 Fo llo w up Sudden Cardiac death 3 5.3 1 2.6 31 31. 3 24.190* <0.001* MI 7 12. 3 13 34. 2 24 24. 2 6.630* 0.038* HF 12 21. 1 8 21. 1 53 53. 5 21.795* <0.001* Stroke 2 3.5 1 2.6 15 15. 2 8.306* 0.016* Table 3: Relation between SRS, demographic data, risk factors and clinical outcomes There was statistically significant relation between smoking and SSS (P=0.014) There were statistically significant relation between sudden cardiac death, MI, HF and SSS P=0.001, P=0.002, and P<0.001 respectively, Figure 2. Figure 2: Relation between Summed stress score (SSS) and follow up. There were statistically significant relation between SRS, sudden cardiac death, MI, HF, and stroke with p<0.001, p=0.038, p<0.001 p=0.016 respectively. Correlation analysis was performed utilizing degree of complaint (CCS class), sudden cardiac death, MI and HF, We found that there was positive correlation between CCS class of anginal pain and sudden cardiac death (r=0.166, p=0.026).There was a positive correlation between CCS class of angina pain and MI (r=0.282, p<0.001) There was positive correlation between CCS class of angina pain and HF (r=0.251, p=0.001). Correlation analysis was performed utilizing SRS, sudden cardiac death, MI, HF, and stroke. We found: There was positive correlation between SRS and sudden cardiac death (r=0.344, p<0.001). There was no correlation between SRS and MI. (r=0.121, p=0.094). There was strong positive correlation SRS and HF. (r=0.333, p<0.001) There was positive correlation between stroke and SRS (r=0.200, p=0.005). Also we found There was strong positive correlation between SSS and sudden cardiac death (r=0.396, p<0.001), There was positive correlation between SSS and MI (r=0.142, p=0.049), There is strong positive correlation between SSS and HF (r=0.370, p<0.001); and There was positive correlation between SSS and stroke (r=0.233, p=0.001), Table 3. Univariate and Multivariate Analysis for Variables Associated with MI We found that, typical pain is the most predictive variable for MI (p=0.001, HR=6.100), also, SSS, lung uptake, transient LV dilation, all of them have a predictive value for MI with HR=1.100, 1.115, and 1.401 respectively. On multivariate analysis typical pain is the most predictive (p=0.001 HR=6.100), Tables 4,5. p HR 95% CI LL UL SSS (>8) 0.021* 2.587* 1.151 5.815 Lung uptake 0.046* 1.845* 1.012 3.363 Transient LV dilation 0.039* 1.959* 1.034 3.712 Typical pain <0.001* 0.151* 0.054 0.423 Table 4: Univariate analysis for variables prognostic for MI. On univariate analysis, we found that the following variables were predictors of sudden cardiac death; SSS (p=0.006, HR=15.901), TID of LV (P<0.001, HR=14.492), SRS (P<0.001, HR=10.321), lung uptake (P<0.001, HR=5.844), typical angina pain (P=0.012, HR=3.121) and age (P=0.024, HR=2.217). But on multivariate analysis TID of LV was the most predictor (P=0.041, HR=5.077). p HR 95% CI LL UL Age (≥ 60) 0.024* 2.174* 1.106 4.276 SSS (>8) 0.006* 15.901* 2.175 116.26 SRS (>8) <0.001* 10.321* 3.636 29.30 Lung uptake <0.001* 5.844* 2.795 12.200 Transient LV dilation <0.001* 14.492* 3.468 60.547 Citation: Rafla S, Abdel-Aaty A, Sadaka MA, Elhoda AAA, Shams AM (2018) Predictors of Ischaemia and Outcomes in Egyptian Patients with Diabetes Mellitus Referred for Perfusion Imaging . J Clin Exp Cardiolog 9: 591. doi:10.4172/2155-9880.1000591 Page 4 of 6 J Clin Exp Cardiolog, an open access journal ISSN:2155-9880 Volume 9 • Issue 6 • 1000591
  • 5. Typical pain 0.012* 3.121* 1.289 7.558 Table 5: Univariate analysis for variables prognostic for Sudden Cardiac death. Discussion One of the strengths of nuclear MPI is the abundance of the published literature addressing its prognostic implications, Klocke et al., Iskandrian et al., Bourque et al., and Di Carli et al. demonstrated that MPI is most frequently performed using the nuclear techniques of SPECT and positron emission tomography (PET). When first introduced half a century ago, SPECT and PET were primarily viewed as diagnostic tools. Beginning with the publication of a landmark paper by Brown in 1991, the major role of MPI has shifted from simply detecting CAD to providing relevant prognostic information and aiding in risk stratification and management decisions [17-21]. Prognostic relevance of symptoms versus objective evidence of coronary artery disease in diabetic patients In our study, typical anginal pain and also atypical angina pain both of them were associated with significant scintigraphic parameters, there is statistically significant relation between atypical pain in diabetics and SSS (P=0.001), also there is statistically significant relation between atypical pain in diabetics and SRS. (X=10.491, P=0.004), and there is statistically significant relation between atypical pain and SDS (P=0.018). We found that there was positive correlation between CCS class of anginal pain and sudden cardiac death (r=0.166, p=0.026). There was strong positive correlation between CCS class of angina pain and MI (r=0.282, p<0.001). In Zellweger et al. study of a large, consecutive series of diabetic patients referred for evaluation of possible or suspected CAD showed that silent CAD, as diagnosed by MPS, was found in 39% of patients. The rate of abnormal MPS results did not differ from that of patients with angina or angina like chest pain, in contrast to non-diabetic patients [17]. In our study and in previous studies there is strong correlation between the symptoms and hard and soft cardiac events, but in our study those who had atypical are statistically related only to HF, and this may absence of awareness about atypical presentation of CAD in diabetics, so unfortunately the patients present with heart failure due to misdiagnosis of MI. Prognostic yield of semiquantitative parameters in diabetic patients In our study, we categorize SSS and SRS as normal SSS 0 to 3; mild SSS 4 to 8; and moderate to severe abnormal SSS>9. And this similar to what was done by Kasim et al. [18]. In our study we apply the semiquantitative role, and we found that there is statistically significant relation between SSS and soft and hard cardiac events, as regard sudden cardiac death (X=14.621, p=0.001), also there was statistically significant relation between SSS and MI (X=8.982, p=0.002), more over the most significant relation was between SSS and HF (X=16.771, p<0.001). Also, in our study, there were statistically significant relations between SRS and MI (X=6.630, p=0.038), statistically significant relation between SRS and stroke (X=8.306, p=0.016). Moreover, we found statistically significant relation between SRS and HF (X=21.795, p<0.001). Also we found statistically significant relation between SRS and sudden cardiac death (X=24.190, p<0.001). On applying correlation analysis between SSS and outcomes, we found significant positive correlation between SSS and MI (r=0.142 p=0.049), stroke (r=0.233, p=0.001), but the most significant positive correlation was between SSS and sudden cardiac death (r=0.396, p<0.001) followed by HF (r=0.370, p<0.001). On correlation analysis between SRS and outcomes, we found that the most significant positive correlation with sudden cardiac death (r=0.344, p<0.001), followed by HF (R=0.333, p<0.001). Also there was significant positive correlation between SRS and MI (r=0.333, p=0.094) also positive correlation with stroke (r=0.200, p=0.005). So in our study SSS and SRS, both of them have positive correlation with hard and soft cardiac events especially sudden cardiac death and heart HF. In our study on applying Kaplan Meier survival curve, we found that SSS is a predictor sudden cardiac death (HR=2.682). Also SRS can predict sudden cardiac death (HR=2.66), HF (HR=1.298), and stroke (HR=1.281). This is more severe in our study, when the SSS >8, the rate of sudden cardiac death is 24.8%, and rate of MI is 25.5% but the rate of HF is 47%. Although SSS is the MPI variable that has been most extensively validated for prognosis, SDS may be the best predictor of nonfatal myocardial infarction and is the variable most predictive of subsequent coronary angiography and early revascularization [22,23]. In our study SDS ranged from 0 to 24.0 with mean ± SD=5.23 ± 4.77. Hachamovitch et al. demonstrated that SDS can be calculated as the percent myocardium ischemic by dividing SDS by 68 (17 segments with a maximal score of 4 per segment) × 100. Using the 17 segment model, a SDS score of 7 is equivalent to 10% of the myocardium ischemic. In his study this threshold was demonstrated to represent the amount of ischemic myocardium necessary to demonstrate an improvement in outcome in patients treated by revascularization vs. those treated with medications alone [24]. Transient ischaemic dilation of LV Petretta et al. demonstrated that TID of LV provides additional value over clinical and perfusion data to identify the presence of severe CAD in diabetic patients. When abnormal TID was considered in addition to summed stress score the sensitivity for diagnosing the diabetic patients with severe CAD improved without reducing specificity. TID of LV was used to reclassify patients with borderline perfusion defects (summed stress score between 3 and 7) [23]. In our study of 194 diabetic patients, TID of LV was present in 120 patients (61.9%), there was statistically significant relation between TID of LV and dyspnea (X=23.020, p<0.001). On applying Multivariate analysis for parameters associated with HF, TID of LV was the most predictive factor (P<0.001 HR=4.329). Lung thallium uptake On applying univariate, multivariate analysis and Kaplan Meier curve, we found that lung uptake was prognostic to MI, sudden cardiac death, HF, and stroke (HR=1.115, HR=1.552, HR=1.208, and Citation: Rafla S, Abdel-Aaty A, Sadaka MA, Elhoda AAA, Shams AM (2018) Predictors of Ischaemia and Outcomes in Egyptian Patients with Diabetes Mellitus Referred for Perfusion Imaging . J Clin Exp Cardiolog 9: 591. doi:10.4172/2155-9880.1000591 Page 5 of 6 J Clin Exp Cardiolog, an open access journal ISSN:2155-9880 Volume 9 • Issue 6 • 1000591
  • 6. HR=2.576 respectively), these results are in harmony with the previous studies of Iskandrian et al. [25]. We found that TID of LV was strongly prognostic to sudden cardiac death (P=0.041, HR=5.077), and, TID of LV had a prognostic value to MI (HR=1.401). Also it had prognostic value to stroke (HR=9.967). Study limitations 1. This is a single center study. 2. This is an observational study. 3. No available registry data about the duration of DM and the degree of glycemic control. 4. Follow up data was not available in 53 patients, i.e. about 27%. However, the results through light on predictors of MACE in Egyptian diabetic patients. Conclusion Semi-quantitative parameters such as SSS, SRS, SDS and percentage of ischaemic myocardium are independent predictors of MACE in both symptomatic and asymptomatic diabetic patients, also non- perfusion parameters such as TID of LV and lung uptake were found to have strong prognostic yield in diabetic patients. 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