Presence of Angina Pectoris Is Related to Extensive Coronary Artery Disease in Diabetic Patients

Abstract

Background

Due to sensorial autonomic neuropathy, the type and severity of angina pectoris in patients with diabetes mellitus (DM) may be rather different from the type and severity of angina pectoris in patients without DM.

Hypothesis

The aim of the study was to understand if angina pectoris is related to extensive coronary artery disease (CAD) in patients with DM.

Methods

The study included 530 patients with DM who underwent coronary angiography at our center in 2009 and 2010. Patients were divided into 4 groups according to type of chest pain: group 1, noncardiac chest pain or no pain; group 2, angina equivalent; group 3, atypical angina; and group 4, typical angina. All angiograms were re‐evaluated and Gensini scores were calculated. Three‐vessel disease was diagnosed in the presence of stenosis >50% in all 3 coronary artery systems.

Results

There were no statistically significant differences between the groups with regard to age, sex, systolic or diastolic blood pressures, body mass index, creatinine clearance, or lipid profile. Fasting blood glucose was significantly higher in group 4 than in group 2. Gensini scores were not statistically different between groups 1 and 2 or between groups 3 and 4; however, the scores for groups 3 and 4 were higher than the score for either group 1 or group 2. Prevalence of 3‐vessel disease was significantly higher in groups 3 and 4 compared with the other groups.

Conclusions

The presence of angina pectoris was related to extensive CAD in patients with DM. The extent of CAD was not correlated with the type of angina (typical or atypical).

Introduction

Coronary artery disease (CAD) is the leading cause of death for patients with diabetes mellitus (DM).1 The prevalence of CAD is higher among patients with DM than among those without DM.2 The cardiovascular mortality rate is more than doubled for men with DM and more than quadrupled for women with DM, compared with their nondiabetic counterparts.1, 2 Coronary artery disease is usually more advanced at the time of diagnosis and has a worse prognosis in patients with DM.3

Due to sensorial autonomic neuropathy, the type and severity of angina pectoris in patients with DM may be different from that which occurs in patients without DM. Ischemia may present as atypical angina or an angina equivalent (exertional dyspnea), or it may occur entirely asymptomatically (silent ischemia) in the diabetic population.4 It has been proposed that the presence of silent ischemia may explain the late diagnosis of CAD in patients with DM. Silent ischemia occurs more often in patients with DM than in nondiabetic patients (6.4%–22% and 2.5%–11%, respectively).5, 6

The character of chest pain is very important in predicting the pretest likelihood of obstructive CAD and determining disease severity.7, 8 The aim of this study is to evaluate the relationship between angina symptoms and the severity of CAD in patients with DM.

Methods

Study Population

The study group was retrospectively recruited from patients who had undergone coronary angiography at our center between January 2009 and December 2010. Of that total, 530 of the subjects had DM and were included in the study. Patients with systemic illness, severe liver or renal insufficiency, acute or chronic inflammatory disease, malignancy, morbid obesity, prior coronary revascularization, or who had experienced acute coronary syndrome within 1 month prior to coronary angiography were excluded from the study. Patient age, sex, smoking habits, past history of disease, and current medications were carefully ascertained. Body mass index (BMI) was calculated as weight/height² (kg/m²).

Patients were divided into 4 groups according to their type of chest pain: group 1, noncardiac chest pain or no pain; group 2, angina equivalent; group 3, atypical angina; and group 4, typical angina. Typical angina is defined as (1) substernal chest discomfort with a characteristic quality and duration that is (2) provoked by exertion or emotional stress and (3) relieved by rest or nitroglycerine.9 Atypical angina meets 2 of the above characteristics. Noncardiac chest pain meets 1 or none of the typical angina features. Angina equivalents included symptoms of other myocardial ischemia, such as shortness of breath, exertional dyspnea, exertional fatigue, nausea, or unexplained diaphoresis.10, 11, 12

The present study was a single‐center study. All examinations were performed by the cardiology clinic. All subjects gave their informed consent, and the study protocol was approved by the ethics committee at our institution. This investigation was in accordance with the Declaration of Helsinki.

Laboratory Measurements

Peripheral venous blood samples were drawn from each patient after overnight fasting. Serum levels of fasting blood glucose (FBG), creatinine, total cholesterol, high‐density lipoprotein cholesterol, low‐density lipoprotein cholesterol, triglycerides, and hemoglobin were measured using conventional methods.

Assessment of Coronary Stenosis by Coronary Angiography

An elective diagnostic coronary angiography (Artis zee; Siemens, Erlangen, Germany) was performed on all of the subjects. Coronary angiograms were evaluated by 2 different experts, and mean values were used to assess the severity of stenosis. Obstructive CAD was defined as stenosis of ≥50% of the diameter of a major epicardial or branch vessel >2.0 mm in diameter. Three‐vessel disease was defined as stenosis of ≥50% in each of the major vessels or their major branches. Gensini scores were calculated for each patient as defined previously.13 Patients were evaluated and treated according to the current guidelines.

Statistical Analysis

Statistical analysis was performed using SPSS for Windows version 15.0 (SPSS Inc, Chicago, IL). For normally distributed variables, mean and standard deviation (SD) are listed. Otherwise, median values are given. The differences in variables among the groups were assessed using either 1‐way analysis of variance (ANOVA) or Kruskal‐Wallis ANOVA, with multiple comparisons made using the Bonferroni test in case of global statistical significance (as indicated). Proportions were compared using the χ² test. Correlations were determined using the Spearman test. P values <0.05 were considered statistically significant.

Results

There were no differences between the groups with regard to age, sex, hypertension, dyslipidemia, peripheral artery disease, prior stroke or myocardial infarction, or smoking habits (Table 1). The number of patients undergoing clopidogrel therapy was significantly higher in groups 3 and 4 compared with group 2, and in group 3 compared with group 1. The proportion of patients undergoing calcium channel blocker therapy was significantly higher in groups 3 and 4 compared with group 2. There were no significant differences in systolic and diastolic blood pressures, BMI, hemoglobin, creatinine clearance (CrCl), or lipid profile. Fasting blood glucose levels were significantly higher in group 4 compared with group 2 (Table 1).

Table 1.

Demographic Characteristics of and Biochemical Results for the Study Groups

Variables	Group 1, n = 54	Group 2, n = 138	Group 3, n = 100	Group 4, n = 238	P Value
Age, y	60 ± 9	60 ± 9	60 ± 9	61 ± 9	0.299
Male sex	25 (46)	64 (46)	37 (37)	114 (48)	0.319
Hypertension	41 (76)	114 (83)	83 (83)	189 (80)	0.639
Dyslipidemia	31 (57)	73 (53)	57 (57)	146 (61)	0.455
PAD	1 (2)	6 (4)	0 (0)	8 (3)	0.212
Prior stroke	2 (4)	6 (4)	9 (9)	8 (3)	0.156
Prior MI	11 (20)	31 (23)	20 (20)	72 (30)	0.119
Smoking	10 (19)	24 (17)	20 (20)	54 (23)	0.645
Medications
ASA	42 (78)	97 (70)	72 (72)	187 (79)	0.266
Clopidogrel	5 (9)	11 (8)	22 (22)a, b	43 (18)a	0.007
ACEI	24 (44)	66 (48)	40 (40)	110 (46)	0.663
ARB	12 (22)	41 (30)	35 (35)	56 (24)	0.121
β‐Blocker	36 (67)	70 (51)	49 (49)	138 (58)	0.098
CCB	7 (13)	14 (10)	23 (23)a	44 (19)c	0.041
Statin	21 (39)	39 (28)	33 (33)	92 (39)	0.196
SBP, mm Hg	130 (120–138)	130 (120–140)	130 (120–140)	130 (120–140)	0.907
DBP, mm Hg	80 (75–88)	80 (80–90)	80 (80–80)	80 (70–80)	0.400
BMI, kg/m2	28 (25–31)	27 (25–31)	27 (25–29)	27 (25–31)	0.656
FBG, mg/dL	144 (103–206)	136 (117–188)	157 (115–221)	169 (120–234)a	0.007
Hb, mg/dL	13.3 ± 1.5	13.1 ± 1.5	13.0 ± 1.6	13.4 ± 1.4	0.053
CrCl, mL/min	97 ± 29	97 ± 33	96 ± 35	96 ± 32	0.971
TC, mg/dL	198 (160–237)	191 (165–228)	193 (158–225)	190 (157–228)	0.807
LDL‐C, mg/dL	120 (93–152)	115 (97–143)	109 (89–144)	115 (91–146)	0.784
HDL‐C, mg/dL	44 (36–51)	42 (35–51)	42 (35–50)	41 (34–49)	0.323
TG, mg/dL	174 (121–217)	141 (104–229)	163 (117–244)	157 (116–223)	0.377

Abbreviations: ACEI, angiotensin‐converting enzyme inhibitor; ARB, angiotensin II receptor blocker; ASA, aspirin (acetylsalicylic acid); BMI, body mass index; CCB, calcium channel blocker; CrCl, creatinine clearance; DBP, diastolic blood pressure; FBG, fasting blood glucose; Hb, hemoglobin; HDL, high‐density lipoprotein cholesterol; LDL‐C, low‐density lipoprotein cholesterol; MI, myocardial infarction; PAD, peripheral artery disease; SBP, systolic blood pressure; SD, standard deviation; TC, total cholesterol; TG, triglycerides.

Data are presented as n (%), mean ± SD, and median (interquartile range).

^a P < 0.01 vs group 2.

^b P < 0.05 vs group 1.

^c P < 0.05 vs group 2.

The total Gensini scores were not significantly different for group 1 compared with group 2, or group 3 compared with group 4; however, the scores for groups 3 and 4 were significantly higher than those for either group 1 or group 2 (Table 2). Similar differences were also seen in Gensini scores calculated for each vessel. The proportion of patients with obstructive CAD was significantly higher for groups 3 and 4 compared with group 2. The percentage of patients with 3‐vessel disease was significantly higher for groups 3 and 4 than for either group 1 or group 2 (Table 2). The total Gensini scores, obstructive CAD, and 3‐vessel disease were significantly higher for men than for women (Table 3). Patients with FBG >130 mg/dL had higher total Gensini scores, obstructive CAD, and 3‐vessel disease (Table 3).

Table 2.

Severity of CAD

Variables	Group 1, n = 54	Group 2, n = 138	Group 3, n = 100	Group 4, n = 238	P Value
Gensini score
Total	14.3 (1.5–32.5)	12.5 (2.3–44.5)	30.8 (7.5–69.5)a	29.0 (7.5–63.0)b	<0.001
LAD	5.3 (0.0–13.8)	3.8 (0.5–13.5)	7.0 (2.5–26.0)a	9.5 (3.0–26.0)b	<0.001
Cx	2.5 (0.0–26.0)	2.0 (0.0–8.5)	5.0 (1.0–16.0)c	3.5 (1.0–12.0)c	0.006
RCA	1.0 (0.0–4.0)	2.0 (0.0–10.5)	4.0 (1.0–20.0)c	4.0 (1.0–14.0)b	0.001
Obstructive CAD	33 (64)	65 (50)	67 (67)d	162 (70)e	<0.001
3‐Vessel disease	6 (12)	20 (15)	28 (29)c	54 (24)c	0.020

Abbreviations: CAD, coronary artery disease; Cx, circumflex coronary artery; LAD, left anterior descending coronary artery; RCA, right coronary artery.

Data are presented as n (%) and median (interquartile range).

^a P < 0.01 vs groups 1 and 2.

^b P < 0.001 vs groups 1 and 2.

^c P < 0.05 vs groups 1 and 2.

^d P < 0.01 vs group 2.

^e P < 0.001 vs group 2.

Table 3.

Subgroup Analysis of Severity of CAD

Variables	F, n = 290	M, n = 240	P Value	FBG Group 1, n = 187	FBG Group 2, n = 343	P Value
Gensini score, total	11.5 (2.5–45.0)	32.0 (9.8–59.3)	<0.001	9.5 (2.5–43.0)	28.0 (7.0–59.3)	<0.001
Obstructive CAD	159 (55)	177 (74)	<0.001	91 (50)	236 (72)	<0.001
3‐Vessel disease	54 (19)	63 (26)	0.037	28 (15)	80 (24)	0.017

Abbreviations: CAD, coronary artery disease; F, females; FBG, fasting blood glucose; M, males. The FBG groups were formed according to FBG levels (group 1, ≤130 mg/dL; group 2, >130 mg/dL).

Data are presented as n (%) or median (interquartile range).

Total Gensini scores were positively correlated with age (r = 0.271, P < 0.001) and FBG (r = 0.228, P < 0.001) and negatively correlated with CrCl (r = −0.288, P < 0.001) and BMI (r = −0.111, P = 0.01).

Discussion

The main finding of this study is that angina pectoris was related to more extensive and complex coronary lesions in patients with DM. The extensiveness of CAD was not based on the type of angina (typical or atypical).

It has been demonstrated that the character of chest pain is very important in diagnosing CAD.7, 8, 14 Large‐scale registries have concluded that Bayesian analysis, including the parameters age, sex, and type of chest pain, effectively evaluates the pretest likelihood of CAD in most cases.7, 8, 15 Following Bayesian analysis, patients having a high probability (>90%) of obstructive CAD may be referred to diagnostic coronary angiography without any further evaluation, whereas noninvasive testing is required for patients with intermediate pretest probability of obstructive CAD (10%–90%).9 Pretest probability particularly increases in high‐risk symptomatic patients (patients with DM, smokers, and patients with hyperlipidemia).15 It has also been determined that the type of chest pain is associated with the severity of CAD.14 Patients with typical angina pectoris are more likely to have left‐main or 3‐vessel disease than patients with atypical angina or noncardiac chest pain.8

Coronary artery disease appears more often in patients with DM because the pathogenesis of DM involves both direct vascular damage and endothelial dysfunction caused by hyperglycemia and hypertension, dyslipidemia, and increased thrombogenesis.16 As a clinical result, CAD is responsible for 75% of deaths among patients with DM, and 30% of patients with acute coronary syndrome have DM.17, 18 It has been proposed that cardiac autonomic neuropathy (CAN) is indirectly responsible for the increased prevalence of CAD and high mortality rates. Cardiac autonomic neuropathy is estimated to occur in approximately 20% of diabetic patients.19 Due to the impaired perception of angina and silent ischemia caused by CAN, diagnostic problems and treatment delays may occur.16, 20 Moreover, it is less likely to stop the exercise by the patient because of ST depression during exercise testing.20 In our study, the absence of significant differences between typical and atypical angina groups in obstructive CAD and disease severity might be attributed to impaired angina perception in patients with DM. We also found that the rates of obstructive CAD in typical and atypical angina groups were statistically higher than in the angina equivalent group, but not statistically different from the noncardiac chest pain or no chest pain group. These results might be caused by a high number of patients with silent ischemia in the noncardiac pain or no pain group. Unfortunately, this speculation cannot be confirmed without knowing the exact number of patients with silent ischemia in the study groups.

In the Bypass Angioplasty Revascularization Investigation 2 Diabetes trial (BARI 2D), the investigators did not find any relation between symptoms and disease severity for women or men with DM.12 In our study, angina was strongly related to disease severity for both sexes. In the BARI 2D trial, patient groups were formed differently than they were formed in our study. The BARI 2D patients with atypical angina and angina equivalent were combined into a single group. When we rearranged our groups similarly to those of BARI 2D, we did not find any differences between group 1 and the atypical angina and angina equivalent group as far as Gensini scores, obstructive CAD incidences, or 3‐vessel disease incidences. We also found that the typical angina group had higher Gensini scores and obstructive CAD incidence than the other groups, but a similar rate of 3‐vessel disease. Regardless, our study results were different from BARI 2D. Keeping in mind that the aim of our study was to evaluate the relationship between the angina symptoms and the severity of CAD in patients with DM, we divided patients into as many different groups as possible according to their symptoms. The difference between our study and the BARI 2D trial may also be due to the retrospective design of our study. Although the records are kept in detail, some inaccuracies might have been included. On the other hand, the BARI 2D trial found that women had less obstructive CAD than men. This finding was in parallel with ours.

According to treatment goals in adult DM, FBG should be <130 mg/dL.21 In our study, the mean FBG values were higher than the target level in all of the groups. Moreover, FBG was significantly higher for group 4 than for group 2 and significantly correlated with Gensini score. When we divided the patients into 2 groups according to target FBG level, we found that the group with impaired blood glucose control had more advanced CAD, as expected. It is known that the degree of hyperglycemia is strongly related to CAD severity and increased risk of cardiovascular events.22 The relatively higher FBG levels in our study population may be related to the withdrawal of oral antidiabetic drugs either preprocedurally by physicians (especially metformin) or voluntarily by patients themselves.

The character of chest pain is not solely based on the severity of atherosclerosis alone. Many confounding physiologic and anatomic factors exist that may influence the degree of angina symptoms, such as the duration of DM, patient pain threshold, position of coronary collateral flow, degree and position of coronary lesions, amount of myocardial demand, and use of medications that may attenuate symptoms. Therefore, the potential effects of these variables on the outcome must be taken into account before reaching a final conclusion.

The present study was limited to an assessment of symptoms based on information recorded on examination forms. The absence of the duration of DM is one of the limitations of our study. The duration affects both the altered angina threshold, caused by more advanced autonomic neuropathy, and the severity of CAD. We also did not evaluate cardiac autonomic functions. Additional information would be obtained about the relation between the symptoms and disease severity among patients with or without CAN if we evaluated cardiac autonomic functions. In addition to the assessment of CAN, the general diabetic autonomic neuropathy should be also evaluated before reaching the final conclusion.

Conclusion

Angina pectoris was related to more extensive and complex coronary lesions in patients with DM. The extent of CAD was not determined by the type of angina (typical or atypical). Women with DM had less obstructive CAD than did men with DM. There was a relationship between FBG levels and CAD severity. Additional studies are needed to understand the degree to which autonomic functions affect the severity of CAD in patients with DM.