Abstract:


            Background

                  Silent Myocardial ischemia was a focus of interest in the last decades. In diabetic patients autonomic neuropathy was blamed for absent anginal pain during ischemic episodes.


            Aim

                   This study was planned to investigate the frequency of silent myocardial ischemia in diabetic patients with autonomic neuropathy and without. Testing the correlation between silent myocardial ischemia and diabetic autonomic neuropathy.

            Methods

                   Five standard autonomic function tests and resting electrocardiography were performed for 82 type II diabetic patients, 45 of them had performed exercise electrocardiography and considered in finding the frequency of silent myocardial ischemia among diabetic patients and its correlation with diabetic autonomic neuropathy.

            Results

                  
                    Autonomic neuropathy found in 34(41.4%) patients of the evaluated 82 patients.  
                    Resting electrocardiographic changes suggestive of silent ischemia were found in 9(11%) of all diabetic patients, 7(77.7%) of them had autonomic neuropathy.
                     Silent Myocardial ischemia as detected by exercise electrocardiography was shown in 12(26.6%) of diabetic patients in general, 8(66.7%) of them had autonomic neuropathy.
                     A statistically significant correlation was found between silent myocardial ischemia (whether detected by resting or exercise electrocardiography) and diabetic autonomic neuropathy (p = 0.019, 0.016), respectively.

            Conclusions


These results are consistent with the concept that autonomic neuropathy (which is fairly common in diabetics) may mask anginal pain and thus obscure the presence of ischemic heart disease.
Diabetic patients with autonomic neuropathy are at risk to have silent ischemic event(s), so screening with resting and / or exercise electrocardiography is needed.

           
Introduction

        Since the mid-eighties of the last century the clinical importance of Silent Myocardial Ischemia (SMI) is well-established(1). Two forms of SMI are recognized(2): the first and less common form designated Types I SMI: occurs in patients with obstructive coronary artery disease (CAD); who do not express anginal pain at any time. The more frequent form Type II SMI: referred to episodes of ischemia with out chest discomfort in between frank anginal attacks when these patients monitored appropriately. So it has become apparent that anginal pain is poor indicator and under-estimator of the frequency and degree cardiac ischemia (3).
          SMI exhibits a circadian pattern and can be triggered by both physical and mental stress (4).

The potential mechanisms of Type I SMI are:


1. The association between diabetes mellitus (DM) and both SMI and "painless" infarction has been attributed to autonomic neuropathy(2, 5-8). Abnormalities of pain perception may be linked in particular to sympathetic denervation (9,10).
2. Higher threshold for pain (2).
3. Some patients produce an excessive quantity of endogenous opoids (Endorphins)(2).

        Longitudinal studies of SMI have demonstrated an increased incidence of coronary events (sudden death, infarction and angina) in asymptomatic patients with positive exercise test(11). Asymptomatic CAD may present with Arrhythmia or heart failure (12).
      Such patients with SMI may be identified prior to such event by an abnormal electrocardiograph (ECG) occasionally at rest (12,13), more commonly during exercise (2,3,13-15), ambulatory Holter monitor (2,14), or by means of coronary arteriography performed as a result of positive exercise test (2, 3, 14).
      Resting ST-T wave abnormalities have been associated with an increased risk of adverse cardiac events, because increased myocardial ischemia represents a possible mechanism for these abnormalities (16).
     SMI can be detected as asymptomatic depression of the ST-segment during exercise testing (12,15). Its presence is associated with an increased risk of early death (12,13). The outcome being significantly worse in those with diabetes (12,15). Greater ST depression involving multiple leads or anginal type chest pain induced by exercise testing denoted more extensive ischemia (2).
    Diabetic Autonomic Neuropathy (DAN) is associated with increased incidence of SMI, silent myocardial infarction and sudden arrhythmic death (17,18). Subclinical autonomic nerve damage occurs widely in diabetics and assumes greater importance in view of increased morbidity and mortality (19, 20). Symptomatic DAN carries a worse prognosis than subclinical DAN (19).
     Cardiovascular Diabetic Autonomic Neuropathy (CDAN) can be detected by certain simple and reliable tests based on cardiovascular reflexes (1,19,&21).
     Pharmacological agents that reduce or abolish episodes of symptomatic ischemia i.e nitrate, b-blocker and calcium antagonists also reduce or abolish episodes of silent ischemia (22,23). It is reasonable to assume that asymptomatic ischemia has a significance similar to symptomatic ischemia that their management with respect to coronary angiography and revascularization should be similar (2,24).

Aim of the Study


       To study the relation of diabetic autonomic neuropathy to the silent myocardial ischemia.


Patients and Methods :
 

        Patients:
  

       A total number of 82 patients known to have Type II diabetes (on oral antidiabetic medications) were included in this study: 34 males (41.4%) and 48 females (58.6%). Ages (30-76) years mean (55.5) years. Duration of diabetes (1-30) years with mean (6.7) years.
       Those patients were studied in the diabetes clinic at Ibn-Sena hospital in Mosul between Dec. 2000 and Aug. 2001.
      For all patients appropriate history was taken, related clinical examination was done and study protocol paper was filled (Appendix 1). Exclusion criteria were patients with:

1. Clinical evidence of prior CAD, other intrinsic heart disease and uncontrolled hypertension.
2. Respiratory disease and sever anemia.
3. Chronic medication with drugs known to cause ST-T wave changes (especially Digoxin and
    Diuretics), or to affect autonomic function.
   The main points in the inquiry had included risk factors for CAD and symptoms suggestive of autonomic dysfunction (Appendix 1).

 

        Methods:
 

       Autonomic function tests were conducted on all patients and all had resting electrocardiography (ECG).
       For all patients with normal resting ECG (69 patients), an appointment for exercise ECG testing (EET) was given, the remaining 13 patients who were not offered EET are : 9 patients found to have resting ECG changes suggestive of silent ischemia and 4 patients were excluded from EET because of some limitations such as: amputation of a leg, intercurrent pyelonephritis, deep vein thrombosis and extreme obesity. Of the 69 patients offered the exercise test, 45 patients had attended the test and 24 patients did not.
        Those who had completed the study plan (45 patients) were considered in diagnosing SMI as detected by exercise ECG whereas the total 82 patients were considered in finding the frequency of CDAN and resting electrocardiographic abnormalities suggestive of silent ischemia.

       A. Autonomic Function Tests

      The following five standard cardiovascular Ewing tests were used for assessment of CDAN. All these tests were conducted in conformity with methods described by Ewing and Clarke (19, 21).

1. Heart rate (R-R interval) variation during deep breathing: The patient sit quietly and then breathes deeply and evenly at 6 breaths per minute, with 5 seconds allocated for each inspiration and expiration to optimize the sinus arrhythmia. An electrocardiogram was recorded throughout the period of deep breathing with a marker to indicate the onset of each inspiration and expiration. The maximum cycles were measured with a ruler. The E: I ratio for each cycle was done and the results was then expressed as the mean E.I. ratio (25), (Appendix 2).

2. Heart rate response to Valsalva maneuver: The test was performed by the patient blowing into mouthpiece connected to a modified sphygmomanometer and holding it a pressure of 40 mm Hg for 15 seconds, while a continuous electrocardiogram was recorded. The maneuver was performed two to three times (depending on patient's compliance) with one minute interval inbetween. The result was expressed as the Valsalva ratio which is the ratio of the longest R-R interval after the maneuver to the shortest RR during the maneuver, measured with a ruler from the electrocardiogram trace. The mean of the three (two) Valsalva was taken as the final value (Appendix 2).

3. Immediate heart rate response to standing: The test was performed with the patient lying quietly on a couch while the heart rate was recorded continuously on electrocardiograph, the patient was then asked to stand up, and the point at starting to stand was marked on the electrocardiogram. The longest R-R intervals at or around the 30th beat as well as that of the 15th beat after starting to stand were measured with a ruler. The characteristic heart rate response was expressed by the 30: 15 ratio (Appendix 2).

4. Blood pressure response to standing: The test was performed by measuring the patient's blood pressure with a sphygmomanometer while he/she was lying down and again when he/she stood up. The postural fall in blood pressure was taken as the difference between the systolic pressure during lying and the systolic pressure after three minutes of standing.

5. Blood pressure response to sustained handgrip: The sphygmomanometer Cuff utilized instead of dynamometer in an analogous fashion. The maximum voluntary contraction was first determined using the modified sphygmomanometer Cuff. hand grip was then maintained at 30% of that maximum for as long as possible up to five minutes. Blood pressure was measured three times before and one-minute interval during handgrip. The result was expressed as the difference between the highest diastolic blood pressure during handgrip exercise and the mean of the three diastolic pressures before handgrip began (Appendix 2).

 

       A resting period of 5 minutes was allowed between one test and another. Each test scored (O) for normal (0.5) for borderline and (1) for abnormal results. (Appendix 2).
       The occasional tests, which could not be conducted, were given a score of 0.5 (11 occasions out of 410). The total score of the five tests was used for analysis, patients with a score of three or more were regarded as having definite CDAN (26).

        B. Resting ECG

       Asymptomatic resting ECG changes of planner or down slopping ST depression 1 mm regarded as positive (2).

        C. Exercise Electrocardiography

       A maximum symptom limited exercise ECG test (EET) was performed according to Bruce protocol between (8-11 am) at cardiovascular physiology laboratory of Ibn-Sena teaching hospital. Tests were supervised by the same observers with the same explanations and encouragement given to each subject. Test was terminated at patient request, fatigue, dyspnoea, muscular pain and angina (12, 27). Tests were analysed by the observer who was blinded to patient status except as being diabetic. ST levels were measured manually and ischemic response was defined as > 1 mm down slopping or horizontal depression from baseline occurring 80 ms after the J point for 3 consecutive beats (12). Tests reported as positive or negative.

        D. Statistical Methods

        Chi-square test was used to determine the statistical difference between the groups. Results were considered significant when (p ²0.05).
 

Results

       According to the scoring system of the five cardiovascular Ewing tests (Appendix 2): 34 (41.4%) out of the total 82 patients were diagnosed as having definite CDAN. Whereas among the 45 patients who had performed EET 17(37.7%) found to have definite CDAN.
      Patients with definite CDAN (34 patients) showed more frequent parasympathetic abnormalities 20 (58%) than sympathetic 10 (29.4%) patients. The remaining 4 patients (11.7%) who found to have both sympathetic and parasympathetic abnormalities had long duration of diabetes (mean 13.2 years).
       Symptom(s) suggestive of autonomic neuropathy were found in only 12 (35.3%), the remaining had only postural dizziness (which can be explained on another base) or no symptom ,inspite of definite objective CDAN. The objective CDAN was significantly correlated (p=0.038) with duration of diabetes.
        Resting ECG changes suggestive of SMI were found in 9(11%) of all patients. Another significant correlation (p=0.019) was found between objective CDAN and resting ECG changes suggestive of SMI. (Table 1).
Among the 45 patients who had performed EET 12(26.6%) found to have SMI, one patient who sustained anginal chest pain for the first time during EET was excluded and there was significant correlation between CDAN and SMI (p =0.016). The correlation of the SMI to the age, sex, duration of diabetes or to a multiple cardiovascular risk factors were generally weak (Table 2).
 

 

Discussion
 

     In diabetic patients autonomic neuropathy rather than pain threshold or endorphin level was thought to obscure pain in SMI (17). In the current study the presence of asymptomatic resting or exercise electrocardiographic abnormalities suggestive of ischemia, were significantly associated with diabetic autonomic neuropathy (p=0.019, 0.016 respectively).
     Diabetic Autonomic Neuropathy was found in 34(41.4%) of all patients, parasympathetic involvement was earlier and more frequently seen than sympathetic. The majority (65.7%) of patients with objective CDAN reported no symptom attributed to autonomic dysfunction. Postural dizziness alone had not been taken as a sole symptom to judge the presence of symptomatic DAN, as it could be explained by other factors such as antihypertensive medications. Postural dizziness was not necessarily associated with postural hypotention. Similarly Wu et al.(28) in their study on heterogeneous population of diabetic patients found a poor relation between postural symptoms and postural hypotension. Other investigators (20, 29) had reported the observations of weak association between subjective and objective features of DAN.
     In previous studies in Iraq, the prevalence of DAN was 35% with dominance of parasympathetic involvement according to Al-Obeidy and Al-Araji (Personal communication). Benni and Al-Dabbagh (Personal communication) in their study on Type I diabetes found the prevalence as 56.7%. Al-Ani(30) had reported it as 64.1%, but the mean duration of diabetes among his patients was 8.2 years.
     Niakan(31), et al. and Osullivan et al.(7) in their studies demonstrated that 34.2% and 41% of diabetic patients had CDAN respectively.
     The duration of diabetes was significantly correlated (p = 0.038) with the presence of objective CDAN. This suggests that prolonged diabetes is a predictor for development of DAN. Unlike some other investigator, the present study did not find a significant correlation between duration of diabetes and SMI (as detected by EET), this could be due to low yield of EET in detecting SMI in comparison to other tests or probably because the known duration of Type II diabetes is not always precise. Thomas (32) et al found the duration of diabetes (Type I) as independent predictor of SMI (as judged by an abnormal myocardial perfusion scintigraphy). Janad Delenne et al. (33) advised screening for SMI in Type II diabetic patients with duration (10 years).
       Resting ECG changes suggestive of SMI were found in 9(11%) of patients, 7(77.7%) of them had CDAN. There was statistically significant correlation between asymptomatic resting ECG changes suggestive of myocardial ischemia and objective CDAN (p=0.019). Taking in consideration, the previously suggested (34) correlation between DAN and prolonged QT intervals, resting ECG will assume an additional importance in assessing potential cardiovascular risks in such patients. In one population-based study (35) (included 2233 men and women) had found resting ECG abnormalities suggestive of asymptomatic CAD were more prevalent among Type II diabetics than others.
     Silent myocardial ischemia as detected by positive EET was found in 12 (26.6%) of patients, 8 (66.7%) patients of them had definite CDAN. The correlation of SMI with CDAN was shown to be significant (p = 0.016).
     Surprisingly, in this study, there was no significant correlation between SMI and other major risk factors for overt CAD like: old age, male sex and multiple cardiovascular risks (at least two of : BMI> 30, hypertension, smoking and family history of CAD) Table 2.

      Depending on the observation of statistically significant correlation between CDAN and SMI, this suggests that DAN is a predictor of SMI and one can expect to find objective CDAN in asymptomatic diabetic patient with positive resting or exercise ECG.
      In general, these findings go with agreement with O'Sulliven(7) et al who found the prevalence of CDAN as 41% and 64.7% of them had SMI (as judged by 24 hour ambulatory ECG). Naka (6) et al. had shown the prevalence of SMI in diabetics as 30% in general and 67.4% of them had CDAN. Unlike the present study, Nestrow(36) et al concluded that SMI (as detected by Thalium 201 scintigraphic abnormalities) were most frequent in diabetics with concomitant hypertension and smoking.
 

Conclusion


      In Iraqi Type II diabetic patients objective autonomic neuropathy was fairly common and related to duration of diabetes. Symptoms of autonomic dysfunction were prominent in some, but the majority of affected subjects were asymptomatic. Although the yield of resting ECG in detecting SMI was generally low, but it has an extra advantages in diabetic patients with DAN. Silent myocardial ischemia as detected by resting or exercise ECG was not uncommon in patients with diabetes, but much more common among those with diabetic autonomic neuropathy. A patient with diabetic autonomic neuropathy should have appropriate follow-up.

Recommendations



1. A future study comparing the yield of SMI, with coronary angiography (the Gold Standard) is
   needed.

2. As far as DAN is fairly common and frequently asymptomatic screening with autonomic function
    tests especially for patients with prolonged diabetes seems logical.

3. A patient with DAN is more susceptible to have silent ischemic w-up with resting if not exercise
   ECGs is required.

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