In patients with diabetes mellitus, cardiovascular disease is the principal cause of mortality and chest pain is the most frequent symptom in patients with stable and acute coronary artery disease. However, there is little knowledge concerning the pervasiveness of uncommon presentations in diabetics. The symptomatology of acute coronary syndrome, which comprises both pain and non-pain symptoms, may be affected by traditional risk factors such as age, gender, smoking, hypertension, diabetes, and dyslipidemia. Such atypical symptoms may range from silent myocardial ischemia to a wide spectrum of non-chest pain symptoms. Worldwide, few studies have highlighted this under-investigated subject, and this aspect of ischemic heart disease has also been under-evaluated in the major clinical trials. The results of these studies are highly diverse which makes definitive conclusions regarding the spectrum of atypical presentation of acute and even stable chronic coronay artery disease difficult to confirm. This may have a significant impact on the morbidity and mortality of coronary artery disease in diabetics. In this up-to-date review we will try to analyze the most recent studies on the atypical presentations in both acute and chronic ischemic heart disease which may give some emphasis to this under-investigated topic.

Cardiovascular morbidity is the main cause of death in diabetics. It is predicted that 366 million patients globally will have diabetes mellitus by 2030. As diabetes mellitus progresses, it results in endothelial dysfunction and changes in energy metabolism which lead to atherosclerosis in medium- and large-caliber arteries, creating lesions in coronary, cerebrovascular and peripheral arteries. Additionally, atherosclerotic plaques tend to develop much earlier, advance more swiftly and are more diffuse in diabetic patients than in non-diabetics. These factors contribute to a two to four-fold higher risk of cardiovascular events in diabetics compared to non-diabetics, with cardiovascular disease being the main cause of death. The combined mortality rate due to cardiovascular disease and diabetes mellitus is 245/100000 population for adults aged 30 to 70 years according to World Health Organization report[1-3].

The overall frequency of coronary artery disease (CAD) among diabetics is 55%. To date, 90% of the published studies presenting data on the atypical presentation of chronic and acute ischemic heart disease are carried out in type 2 diabetics, while there are few data available on type 1 diabetics. Consequently, most of our conclusions in this review are for type 2 diabetes[4-6].

Diabetic patients frequently present with silent myocardial ischemia (SMI), and the absence of an imperative clinical “warning symptom”. Statistics from the Framingham study showed that asymptomatic patients with various risk factors have an annual cardiac mortality rate of approximately 3%[4,5,7]. Such outcomes from these studies raise numerous questions regarding diabetes mellitus and CAD: Why is myocardial ischemia repeatedly atypical or silent in diabetic patients? In what way is it discovered? What is its aftermath? How do we deal with it? The current analysis will tackle these issues. We identified studies via searches in MEDLINE, PubMed, EMBASE, and Current Contents and by reviewing reference lists in all the studies performed in the last 30 years from both developed and developing countries using the following keywords: diabetes mellitus, acute coronary syndrome (ACS), acute myocardial infarction (AMI), ischemic heart disease, atypical presentation, and SMI. We attempted to provide conclusions and future perspectives on this under-evaluated topic according to up-to-date studies from different parts of the world.

Chest pain is the cornerstone symptom of ACS. However, data concerning the prevalence of atypical presentation among these patients and its relation to subsequent care is scarce. CAD has specificities in diabetics with pervasive atherosclerosis. Diabetic patients are also more frequently asymptomatic, with a wide range of atypical presentations which makes the diagnosis of CAD challenging. In addition, diabetic patients with CAD have poorer outcomes than non-diabetics. CAD is the foremost source of morbidity and mortality in diabetic patients with higher mortality after an acute cardiac event compared to non-diabetics. Such inconsistencies may be related to the degree of CAD in diabetics, the magnitude of left ventricular remodeling, and the occurrence of significant ventricular dysrhythmias[8-27].

Despite the fact that CAD is the primary vascular complication of diabetes, there is a significant gap in our knowledge and understanding on atypical ACS symptoms in diabetics. Conventional risk factors, such as, hypertension, diabetes, hypercholesterolemia and smoking have a significant impact on the symptomatology of ACS and stable angina, including both pain and non-pain symptoms. Although numerous investigations on diabetes management have been performed, only a few studies have focused on atypical ACS symptoms in patients with diabetes with contradictory results. Diabetics may have a diminished awareness of ischemic chest pain which could result in an uncharacteristic presentation. This may be explained by autonomic neuropathy and prolongation of the anginal perceptual threshold[28]. In addition, diabetic patients with SMI have evidence of a disseminated abnormality in metaiodobenzylguanidine uptake on positron emission tomography. A similar finding was also observed in asymptomatic diabetic patients on stress testing with a dipyridamole stress myocardial scan and contrast echocardiography in approximately 60% of diabetic patients, these findings reflect abnormal pain perception interrelated with sympathetic denervation[29]. SMI is seen more frequently in diabetic patients than in the general population. SMI may be the main atypical presentation observed in major clinical trials compared to other forms of atypically presented CAD in both acute and chronic forms. However, the exact prevalence of SMI remains unidentified[30]. In general, the frequency of silent CAD diverges according to the test used and the patient population investigated. The prevalence of silent CAD is 6%-23% in low-risk diabetics, and can be as high as 60% in high-risk diabetic patients. Recently it was recognized that silent CAD has a similar prognosis and adverse events rate when compared with symptomatic CAD[31]. Possible explanations for the dissimilar symptoms in patients with diabetes mellitus, comprise central mechanisms such as altered thresholds of pain sensitivity, beta-endorphin levels, in addition to autonomic neuropathy resulting in sensory denervation. The American Diabetes Association states that patients with symptomatic autonomic neuropathy are at increased risk of sudden death; however, it still controversial whether there is adequate scientific data available to indicate that cardiac autonomic neuropathy contributes to silent ischemia and whether specific diabetic patients might gain benefit from routine testing for occult ischemia[31].

In the last few years, diabetics have not experienced the same decline in CAD-related mortality as non-diabetics. The poor prognosis associated with diabetes after AMI has been witnessed in several studies despite adjustment for age, sex, coronary risk factors[12,13,15-20] and associated comorbidities[32]. Contradictory evidence is available concerning the morbidity and mortality of diabetic patients managed with insulin vs oral hypoglycemic agents or diet after AMI[12,18,27,32,33]. Similarly, uncertainty still exists regarding the negative prognostic implications of diabetes in patients with a different spectrum of ACS i.e., unstable angina, non-ST and ST-segment elevated AMI. It is imperative to establish whether these patients are consistently receiving proven cardiac interventions under current practices.

Silent myocardial infarction/ischemia (SMI) is more frequent than formerly thought. Up to 25% of patients with CAD have suffered silent SMI; the magnitude of the myocardium affected is on average 10% of the left ventricle muscle mass, and it is more prevelant in diabetics. The phenomenon of SMI is still debatable. The presence of cardiac autonomic dysfunction is the assumed factor that influences the frequency of SMI in diabetics[34]. Hence, the importance of identifying individuals with a high risk for cardiovascular events, prior to symptom onset may be of significance. Diabetes mellitus affects vascular endothelium, causing endothelial dysfunction[35]. A study assessed the frequency, scope, and independent predictors of SMI in 2 large independent cohorts of consecutive patients without a history of MI referred for rest/stress myocardial perfusion single photon emission computed tomography. One thousand six hundred and twenty-one patients were registered in the derivation cohort and 338 patients in the validation cohort. SMI was diagnosed in patients with a myocardial scar involving ≥ 5% of the left ventricle. In the derivation cohort, 23.3% had SMI. The median infarct size was 10% [interquartile range (IQR) 5%-15%] of the left ventricle. The occurrence of SMI was 28.5% in diabetics vs 21.5% in non-diabetics (P =0.004). Diabetes mellitus was an independent predictor for the presence of SMI (OR = 1.5; 95%CI: 1.1-1.9; P = 0.004). In the validation cohort, the prevalence of SMI was 26.3%, with a higher incidence in diabetics (35.8%) compared to non-diabetics (24%; P = 0.049). The median infarct size was 11.8% (IQR, 5.9%-17.6%) of the left ventricle. After logistic regression analysis; diabetes mellitus was a noteworthy prognosticator of the presence of SMI confirming the derivation cohort result[36].

In a cross-sectional study involving 200 subjects (mean age; 46 ± 10 years, 31 had diabetes), the subjects underwent an exercise stress test. A positive test for silent ischemia was seen in 19% of diabetics and 13% of non-diabetics, which was not statistically significant (P = 0.397). Hypertension and obesity were found more frequently in diabetics (48% vs 27% and 35% vs 18%, respectively)[37]. Blood lipid levels may predict SMI in non-insulin dependent diabetes. A study included 220 asymptomatic diabetics who underwent laboratory tests and gated single-photon emission computed tomography with coronary angiography as the confirmatory test, when gSPECT detected ischemia. A higher level of total cholesterol was seen in gSPECT-positive diabetics, together with low-density lipoprotein (LDL), and triglycerides (P < 0.05). High-density lipoprotein (HDL) levels were lower in this group (P < 0.05). HDL was the most important normalized variable. This study included more men (33.3%) than women (24.8%). HDL levels were significantly lower in these patients. The association between low HDL and high triglycerides was a strong indicator of myocardial ischemia in type 2 diabetics without clinical cardiovascular signs[38]. A gated myocardial perfusion SPECT in asymptomatic diabetics with a high combination of cardiovascular risk factors detected SMI in a significant proportion of patients and this seemed to be related to future coronary events. Diabetic nephropathy may indicate a greater likelihood of abnormal studies[39].

A study evaluated the pervasiveness of SMI in 147 subjects in a diabetic Afro-Caribbean population. 23.1% had SMI; these patients had a personal history of cardiovascular disease similar to those without diabetes. On multivariate logistic-regression analyses, the adjusted odds ratio of SMI was considerably higher in patients with a personal history of cardiovascular disease (4.36, 95%CI: 1.36-13.96; P = 0.01) and left ventricular hypertrophy (LVH) (2.46, 95%CI: 1.03-5.86; P =0.04)[40].

Dobutamine stress echocardiography may be a useful diagnostic test for detecting SMI, especially in diabetic patients at high cardiovascular risk. A study of 79 diabetics (average age = 58.8 ± 11.8 years) revealed that 67.1% had a positive test, with a predominance of motion abnormalities in the anterior area (83%). Microalbuminuria (P = 0.0001), inactivity (P = 0.0001), dyslipidemia (P = 0.0002), arterial hypertension (P = 0.001), smoking (0.003) and male sex (P = 0.004) were the main cardiovascular risk factors associated with positivity[41].

In the detection of ischemia in asymptomatic diabetics (DIAD) study, the largest prospective study with a 4.8-year follow-up period included 1123 asymptomatic persons with type 2 diabetes who were randomized to either testing with stress myocardial perfusion scan or no testing. In this study, 53%-75% of participants with intermediate to high cardiovascular risk had a prevalence of inducible ischemia on screening that ranged from 21% to 24%, which was almost comparable to lower-risk patients (19%-23%). Patients with intermediate-/high-risk had higher rates of cardiac events (only significant for the UKPDS risk engine 4.2 vs 1.2%, P = 0.002). The yearly cardiac event rate was < 1% in all risk groups, apart from the high-risk UKPDS group (approximately 2% per year). Surprisingly the annual cardiac event rate for intermediate/high risk was low and not altered by standard testing for inducible ischemia[42].

High LDL level and higher carotid intima-media thickness are predominant issues that can indicate whether a patient with non-insulin dependent diabetes (NIDDM) is are at risk of SMI. A high carotid intima-media thickness is a substitute and dependable indicator of higher risk of CAD in non-insulin dependent diabetic patients, even in those without evident CAD[43].

Another study determined SMI in 90 unselected middle-aged asymptomatic NIDDM patients (48 men; mean age: 49 ± 6 years, mean diabetes duration of 4 ± 4.2 years (range 1-21 years) without CAD as documented by treadmill exercise test. Four percent of patients had a positive test. Diabetics with SMI were older (55 ± 3 years vs 49 ± 6 years, P = 0.04), had a higher fibrinogen level (372 ± 51 vs 307 ± 71 mg/dL, P = 0.04) and had lower total exercise time and peak workload (375 ± 30 s vs 474 ± 115 s, P = 0.04; 7.3 ± 0.5 vs 8.9 ± 1.9, P = 0.04, respectively). Insulin resistance is related to different atherosclerosis risk factors. Exercise test outcomes showed increased cardiac sympathetic activity and parasympathetic withdrawal in increased insulin resistance[44]. Left atrial surface area independently predicted SMI after adjustment for established echocardiographic and inflammatory risk factors in diabetics[45]. Age and differential pulse pressure may be predictors of SMI[46].

A study estimated the frequency of SMI in 353 asymptomatic Caucasian diabetic patients using the treadmill test with single-photon emission computed tomography and exercise testing or dipyridamole injection with coronary angiography as the confirmation test. Patients with SMI (8.5% were diabetics: 3 IDDM and 13 NIDDM) were older and had autonomic neuropathy, hypertension, dyslipidemia and higher microalbuminuria (613 ± 211 mg/d vs 72 ± 245 mg/d; P < 0.05)[47].

SMI may occur in more than 20% of asymptomatic patients with NIDDM. Conventional and evolving cardiac risk factors were not linked with abnormal stress tests, even though cardiac autonomic dysfunction was a resilient prognosticator of ischemia using adenosine technetium-99m sestamibi single-photon emission-computed tomography myocardial perfusion imaging in asymptomatic NIDDM patients and testing the efficiency of current American Diabetes Association screening guidelines. A total of 1123 patients, with no known or suspected CAD were randomly assigned to either stress testing and 5-year clinical follow-up or to follow-up only. In this study 22% had SMI; the strongest prognosticators for abnormal tests were abnormal Valsalva, male sex, and diabetes duration, but not traditional cardiac risk factors or inflammatory and prothrombotic markers. Choosing only patients who met the American Diabetes Association guidelines failed to detect 41% of patients with SMI[48]. Erectile dysfunction may become a possible indicator to identify diabetic patients with SMI during screening, particularly in patients with additional cardiovascular risk factors[49]. However, diabetics may have a higher prevalence of angina pectoris during daily activity than non-diabetics[50]. Using dobutamine stress echocardiography to detect SMI, significant CAD was identified in 9% of asymptomatic diabetics. Dynamic left ventricular outflow obstruction was detected in 59% of diabetics and in only 22% of non-diabetics, however, these results need to be investigated in future studies[51].

The association between SMI and cardiac autonomic neuropathy has been reported in a few studies (Table 1). Autonomic dysfunction is seen in 85.7% of diabetics with SMI vs 18.7% of diabetics without silent ischemia (P = 0.001). The incidence of SMI was higher in patients with autonomic neuropathy (40% vs 10%) P < 0.001. The duration of diabetes was greater (13 ± 1.59 years) in patients with autonomic neuropathy, and systolic blood pressure was predictive of silent ischemia in diabetics[52-54].

A few other studies[55-65] assessed different aspects of the association between SMI and diabetes (Table 1). Patients with SMI had higher ischemia in the working forearm compared to diabetic patients with and without neuropathy. There is a quantitative and qualitative difference in ischemic tolerance between patients with SMI and patients with diabetic neuropathy[57,58]. The role of beta endorphin in diabetic patients with SMI may be less substantial than in non-diabetics; therefore, diabetic neuropathy which affects the autonomic pain fibers that innervate the heart may be involved in the pathogenesis of SMI in diabetics and appears to be the most probable reason for the absence of pain[59,60].

Many reports including major clinical trials and sporadic studies (Tables 2 and 3) have shown that diabetes mellitus is an independent predictor of atypical presentation of ACS with a controversial outcome[66]. Several studies reported that diabetic patients had less pain compared to non-diabetics[67-75], while other studies found no difference[76-81].

Assuming a greater risk of cardiovascular events and more frequent silent CAD in diabetics compared to non-diabetics, screening asymptomatic diabetic patients for CAD is an attractive concept. Nevertheless, there are many elements against instigating a wide-ranging screening program. Of note is the paucity of confirmed data indicating that a prospectively utilized screening program has a positive prognostic impact in asymptomatic diabetic patients. From the above reviewed studies the incidence of atypical SMI is highly variable. Measures should be taken to manage hypertension and hyperlipidemia exclusively on the basis of diabetes status, devoid of diversity based on the presence or absence of recognizable CAD. From the above available data the studies which used stress single-photon emission computed tomography imaging showed around 50% abnormal images and 20% high-risk images, respectively. However, the DIAD (Detection of Ischemia in Asymptomatic Diabetics) study[42] described a considerably lower percentage of abnormal SPECT images (16%) and images with a very large (≥ 10% of the left ventricle) defect of 1%. We think that it is wise for the clinician to investigate silent and/or atypical myocardial ischemia and this applies to stable CAD in high risk diabetic patients, i.e., patients with long-standing diabetes and diabetic complications such as diabetic neuropathy which may frequently present atypically. We suggest using a test which has high specificity and sensitivity for the detection of myocardial ischemia such as a myocardial perfusion scan and SPECT scan as shown in the above studies. The massive fiscal consequences of investigating all asymptomatic diabetic patients at intermediate and high risk using clinical scoring systems should be considered. Undoubtedly more investigations are required to address these issues.

Not all diabetics have the same coronary risk, therefore, it is important to determine which investigations to perform and for which patients. This strategy is reasonable as it allows identification of patients who require a medical or an invasive (angioplasty vs CABG) procedure, as these interventions may improve the prognosis. Patients with more than two risk factors may need further investigations with exercise stress testing which may provide supporting diagnostic and prognostic data. When exercise stress testing is sub-maximal or non-diagnostic, a second investigation with perfusion myocardial scintigraphy may be warranted bearing in mind that in diabetics this test may not have the same diagnostic accuracy as in the general population, but it is of prognostic value. Ischemia involving over 20%-25% of the myocardium justifies therapeutic investigation. Stress echocardiography is comparable to scintigraphy.

The greater incidence of SMI in diabetics seems to be due to the increased frequency of ischemic heart disease in diabetics. The importance of cardiac autonomic neuropathy in SMI is still debatable, but is the most acceptable cause of SMI, as discussed in the above review, nevertheless studies are sporadic. The risk factors associated with SMI and atypical ischemic syndrome are the usual traditional factors i.e., age, male gender, hypercholesterolemia, hypertriglyceridemia, hypertension, smoking, a family history of cardiovascular disease, insulin therapy (for type II diabetes), proteinuria, retinopathy, and peripheral occlusive arterial disease. Upcoming studies should determine possible approaches to augment the patient subgroup that will possibly benefit from screening with judicious cost-effective analyses. Currently, there are no data to support the use of anti-ischemic medication to improve CAD in diabetic patients.