1. Silent ischemia W. William Heberden’s described in the 1770s of a new syndrome, centering around pain in the left chest and named by him “angina pectoris”. Heberden’s description of the symptoms has prevailed for centuries, as if it were written in stone. Decades later, this “pain in the chest” was clarified as being induced by myocardial ischemia at the time the patient experiences the pain. Circulation..2002:1906-08

2. Silent ischemia James Herrick described in his historical treatise on acute myocardial infarction in 1912 two of his six patients who experienced no pain during their cardiac events. Trans Assoc Am Phys.1912:100 In the 1970s, several groups of investigators began to use ambulatory monitoring of the ECG, and with this new technique, they described that ST depression, a cardinal sign of myocardial ischemia on the ECG, can occur in patients with ischemic heart disease (IHD) without accompanying pain. Ambul And ECG monitoring : 1978:93-106

3. Why Silent Myocardial Ischemia Is Painless In Some Individuals A defective warning mechanism - as the reason for the absence of pain, stressing that sensibility to pain differs from patient to patient. J Am Coll Cardiol. 1983;340-45 Others suggested that a general decreased sensibility to pain is present in clinically silent patients. J Am Coll Cardiol; 1998:348-52 Intriguing observations have shown that there is a particular biochemical pattern of inflammatory system activation (an increased production of inflammatory cytokines) that explains the lack of anginal symptoms in these patients. J Am Coll Cardiol 2001;1895-1901

4. Clinical Relevance of Silent Ischemic Episodes Patients with IHD who have painful anginal attacks during a 24-hour period are most probably having additional painless ischemic episodes, usually triggered by physical exertion or mental stress. Circulation. 2002; 1906-8 In clinical studies, as many as 90% of ischemic episodes were found to be silent. J Am Coll Cardiol. 1998; 1627-34 It has been shown that patients with ambulatory ischemia are more likely to have multi vessel coronary disease than patients without ambulatory ischemia J Am Coll Cardiol.1997:1483-89 Thus, it appears that anginal pain is a poor indicator for IHD because it underestimates the frequency of significant ischemia. Episodes of documented ischemia, regardless of whether they are symptomatic or silent, do have prognostic significance. J Am Coll Cardiol. 2002: 1906-08

5. Silent Ischemia Diagnosis Ambulatory monitoring does provide meaningful information about ischemia in IHD patients, as a potential test for those who are unable to exercise, it can detect Prinzmetal’s variant angina and hidden arrhythmia and assess the effectiveness of antiarrhythmic therapy. Circulation. 1999: 886-93 Because ambulatory monitoring does not appear to be useful for screening or for primary detection of IHD in asymptomatic patients, exercise testing remains the most important screening test for IHD. Circulation. 2002: 1906-08

6. Arthur Master, who introduced exercise testing in the 1930s for detecting myocardial ischemia, tacitly accepted that the occurrence of pain during his classic 2-step test was not a criterion for diagnosing IHD. For many decades,the presence or absence of pain during bicycle or tread meal testing was neglected and usually not even noted on test interpretation. Circulation.2002: 1906-08 The pendulum, however, has now swung to the other side; exercise- induced silent ischemia was recently found to be a most powerful predictor of IHD in men who presented with any of the standard coronary risk factors. J Am Coll Cardiol. 2001: 72-79 Exercise testing can thus identify the high-risk men, even if asymptomatic, who could benefit from risk reduction and preventive measures. Circulation.2002: 1906-08 The Importance of Pain During Exercise Testing

7. Myocardial perfusion defects detected on stress thallium testing or ventricular dysfunction seen on stress echo examinations are today accepted as evidence for transient ischemia, despite the lack of both accompanying ECG alterations and chest pain. Circulation.2002: 1906-08 These tests have provided the final proof for the existence of silent myocardial ischemia and, most importantly, they also have shown that the severity of ischemia detected by these methods is not correlated with the presence or absence of accompanying pain. Clinical Nuclear Cardiology. 1995 The Importance of Pain During New Myocardial Imaging Techniques

8. Myocardial Infarction Without Pain Myocardial infarction (MI) without concurrent chest pain was described in the 1950s in the Framingham heart study. Silent Myocardial Ischemia. 1998:47-53 This possibility should be borne in mind not only by the physician but also by the person who may potentially suffer a heart attack, especially those with risk factors such as diabetes and high blood pressure, since 20% to 60% of MIs are unrecognized by the patient and are diagnosed only subsequently. Of these unrecognized infarctions, approximately half are truly silent (ie, the patient is unable to recall any symptoms whatsoever). Circulation.2002: 1906-08 It is important to stress that the prognosis of patients with silent and with recognized infarctions appears to be similar both for 10-year survival and for subsequent heart failure. Silent Myocardial Ischemia. 1998:47-53

9. Silent Ischemia and diabetes The overall prevalence of CAD among patients with diabetes is higher than in non-diabetic patients and may be as high as 55% among patients with diabetes. Diabetes Care. 1979: 120-6 Furthermore, CAD represents the leading cause of death in patients with diabetes. Diabetes Care. 1993: 2035-8

10. Chest pain represents the “tip of the iceberg” in the ischaemic cascade. Swiss Med Wkly. 2001: 427-32 When diabetics and non-diabetics without evidence of CAD are screened for ischaemia, there is a higher incidence of silent ischaemia in the former, 6.4–22% and 2.5–11%, respectively. Am J Cardiol. 1997: 134-9 Angina pectoris ischemia Ischemia on ECG Systolic Dysfunction Diastolic Dysfunction Metabolic Changes Perfusion defect No Ischemia Silent Myocardial Ischemia

11. Pain response to ischemia is often blunted in diabetes. Patients who presented with silent ischemia and had a CAD at coronary angiography for verification of CAD more often had peripheral macroangiopathy and a higher prevalence of retinopathy. No correlation was found between silent ischemia and duration of diabetes, HbA1c level, renal status, or cardiovascular risk factors except for family history of CAD. Swiss Med Wkly. 2001: 427-32 Langer et al. evaluated the sympathetic innervation in diabetic patients using metaiodobenzylguanidine (MIBG) imaging after having concluded in another study that silent myocardial ischemia in asymptomatic diabetic men occurred frequently & in association with automatic dysfunction, suggesting that diabetic nephropathy might be implicated in the mechanism of silent ischemia. Am J Cardiol. 1991: 1037-8 Why Silent Ischemia

12. Why silent Ischemia ? Altered perception of myocardial ischemia might result from damage to the sensory innervation of the heart. Swiss Med Wkly. 2001: 427-32 Hikita et al. Measured ß-endorphin levels during exercise & compared diabetics with non diabetics. Am J Cardiol. 1993: 140-3 The ß- endorphin level &pain threshold were significantly higher in non diabetic patients with silent ischemia than in diabetics. When myocardial ischemia (whether silent or symptomatic) was present during exercise testing, the long term survival among diabetics was worse than non diabetics. Swiss Med Wkly. 2001: 427-32

13. Why silent Ischaemia ? In general, it has been shown that cardiovascular mortality rate is more than doubled in diabetic men & and raised than 4 fold in diabetic women, when compared with other non diabetic counterpart. JAMA. 1979: 2035-8 When myocardial ischemia (whether silent or symptomatic ) was present during exercise testing, the long term survival among diabetics were worse than that of non diabetics. Swiss Med Wkly. 2001: 427-32 For clinicians, whether & when to examine patients with diabetics who have no clear evidence of CAD poses a difficult question. In type I diabetics, who often present with out the traditional risk factors, duration of diabetes is the most important predictor of premature CAD. Swiss Med Wkly. 2001: 427-32 CONT.

14. Because type 1 diabetes often starts early in life, CAD can occur as early as in the 3rd & 4th decade in life. Diabetes Care. 1998: 1551-9 In contrast,type 2 patients frequently have many other risk factors & usually present in the 5th or 6th decade of life or later. Often, diabetes is first identified when the patient presents with angina, MI, or heart failure. Swiss Med Wkly.2001:427-32 Furthermore, diabetics with silent ischemia may present in an atypical manner e.g. with symptoms of easily fatigability, exertional dyspnoea, or indigestion. Swiss Med Wkly.2001:427-32 Why silent Ischaemia ?

15. Indications for testing patients with diabetes Resting ECG suggestive of ischemia or infarction Peripheral or carotid occlusive arterial disease Sedentary lifestyle, age  35 years, and plans to begin a vigorous exercise programme Two or more of the risk factors listed below in addition to diabetes : Total cholesterol  6.2 mmol/l, LDL  4.0 mmol/l, or HDL <0.9 Blood pressure >140/90 mm Hg Smoking Family history of premature coronary artery disease Positive micro/macroalbuminuria test.

16. Cardiac testing algorithm for the asymptomatic diabetic patient. MI or ischemia on ECG cerebral/peripheral  1 risk factor and or vascular disease abnormal ECG abnormal ECG but no or clear evidence of ischemia  2 risk factors Routine follow up stress perfusion imaging exercise stress test (if not limited by baseline or ECG or inability to exercise) stress echo based on test results +/– coronary angiography

17. Follow up strategies after screening exercise test Pre-test risk exercise test results normal mildly moderately severely abnormal abnormal abnormal high ++ +++ ++++ ++++ 4–5 risk factors moderate + +++ +++ ++++ 2–3 risk factors low + +++ +++ ++++ 0–1 risk factors + Routine follow-up ++ Close follow-up +++ Imaging (myocardial perfusion SPECT or stress echo) ++++ Cardiology referral/possible coronary angiography When initial exercise stress testing is done in asymptomatic diabetic patients, the type of follow-up depends on the pretest risk and degree of abnormality on the stress test. Normal follow-up indicates annual re-evaluation of symptoms and signs of CAD and ECG. A repeat stress test should be considered in 3–5 years if clinical status is unchanged. Close follow-up means shorter intervals between evaluation and follow-up stress test, i.e. 1–2 years. Pretest risk is assigned based on the presence of other vascular disease and risk

18. MANAGEMENT Several questions remain unresolved regarding proper treatment of silent ischemia. The management of diabetic patients with CAD requires a multidisciplinary approach. Management of blood pressure and lipids, smoking cessation, and routine use of aspirin are indicated for all patients with diabetes but arguably will have an even greater impact on morbidity and mortality in patients with ongoingischemia. When aspirin is not tolerated, other anti-platelet agents should be considered, such as clopidogrel. Clinical Diabetes. 2003: 5-9

19. Glycemic control in the management of silent ischemia Glycemic control is the cornerstone for treating and preventing diabeticmicrovascular complications such as retinopathy and nephropathy. Improved glycemic control may also help to lower rates of macrovascular complications such as cardiovascular events. Appropriate glycemic control includes medical nutrition therapy/meal planning, exercise, and pharmacotherapy as needed. Clinical Diabetes. 2003: 5-9

20. ß-blockers in the management of silent Ischemia ß-blockers are arguably the most effective class of anti-anginal medications and are a cornerstone of therapy in suppressing silent ischemia. This class of medications has a favorable effect on myocardial oxygen demand by reducing blood pressure and heart rate. ß- blockers reduce the duration and frequency of silent ischemic episodes more than do other classes of anti-anginal drugs. Clinicians have been reluctant to use ß-blockers in diabetic patients because of the potential dampening symptoms of hypoglycemia or worsening of glycemic control. However, cardioselective ß-blockers should be considered in all diabetic patients with CAD. ß-blockers are associated with prognostic benefits including fewer cardiovascular complications, subsequent infarctions, and deaths, particularly in patients with diabetes. Clinical Diabetes. 2003: 5-9

21. ACE inhibitors in the management of myocardial ischemia ACE inhibitors are known to reduce infarct size, limit myocardial remodeling, and reduce mortality. In diabetic patients, they are also the treatment of choice for proteinuria and hypertension. Proteinuria, in turn, is an indicator for diabetic nephropathy and possibly for advanced atherosclerosis and cardiovascular disease. Clinical Diabetes. 2003: 5-9 Recent studies suggest that ARBs carry similar benefits. Lancet.2002: 1004-10

22. CCBS in the management of silent ischemia Calcium-channel blockers (CCBs) are also effective pharmacotherapy. Similar to the ß-blockers, CCBs reduce the duration and frequency of silent ischemia. This class of medications may be prescribed when the maximal effect of ß-blockers has been achieved or when ß-blockers are contraindicated or not tolerated. Clinical Diabetes. 2003: 5-9

23. Nitrates in the management of silent ischemia Nitrates may be used in oral or transferal routes with -blockers when desirable suppression of silent ischemia is not achieved with ß-blockers alone. The effect of chronic usage of nitrates is limited by tolerance. This limitation can be overcome by allowing an 8- to 10-hour nitrate- free period daily. Clinical Diabetes. 2003: 5-9

24. Psychological and emotional treatment in the management of silent ischemia Treatment of psychological and emotional issues : It is important because psychological stressors may also contribute to precipitating silent ischemia. Recognizing and treating depression is of critical importance. Proper management of such stressors may indeed reduce myocardial ischemia. Clinical Diabetes. 2003: 5-9

25. Revascularisation in the management of silent ischemia Revascularisation as a means of therapy for silent ischemia is not well supported. Coronary revascularisation may be achieved surgically via coronary artery bypass graft (CABG) or percutaneously via percutaneous coronary intervention (PCI). CABG and PCI should be considered in high-risk patients who display ongoing myocardial ischemia despite an adequate trial of pharmacotherapy. Clinical Diabetes. 2003: 5-9