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Professor J. C. Kaski , M.D., D.M ( Hons .), D.Sc., F.E.S.C., F.R.C.P., F.A.C.C.

The Burden of Angina with Normal Coronary Arteries - Management . Professor J. C. Kaski , M.D., D.M ( Hons .), D.Sc., F.E.S.C., F.R.C.P., F.A.C.C. Cardiovascular Biology Research Centre Division of Cardiac and Vascular Sciences. Conflict of interest: Nil to declare. NSTE-ACS.

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Professor J. C. Kaski , M.D., D.M ( Hons .), D.Sc., F.E.S.C., F.R.C.P., F.A.C.C.

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  1. The Burden of Angina with Normal Coronary Arteries - Management Professor J. C. Kaski, M.D., D.M (Hons.), D.Sc., F.E.S.C., F.R.C.P., F.A.C.C. Cardiovascular Biology Research Centre Division of Cardiac and Vascular Sciences Conflict of interest: Nil to declare

  2. NSTE-ACS R Bugiardini et al. Arch Int Med 2006;166:1391-95 Prevalence of Angina with NCA Relatively common Patients with exertional chest pain undergoing diagnostic angiography JC Kaski et al JACC 1995

  3. Angina with Normal Coronary Arteriograms Clinical presentation and pathogenesis Management

  4. Cardiac Syndrome X • Typical exertional/rest chest pain • Ischaemic ECG changes • Normal coronary arteriograms JC Kaski et al. Am J Cardiol. 1986 More prevalent in women; 30% have myocardial ischaemiaand >50% coronary microvasculardysfunction/endothelial dysfunction (1). Prognosis is good in Cardiac SX (2) JC Kaski et al. JACC 1998; JC Kaski. Circulation 2004

  5. Diagnostic uncertainty poses a serious burden on the individual Impaired Quality of Life Psychosocial morbidity ? Prognosis ? Management "Burden“ - Lithograph

  6. Quality of Life is Impaired in CSX • RO Cannon et al. Imipramine in patients with chest pain despite normal coronary angiograms. NEJM 1994; 330:1411-1417 • JC Kaski et al.Cardiac syndrome X: clinical characteristics. Long term follow up study. J Am Coll Cardiol. 1995;25:807-14. • F Atienza et al. Assessment of quality of life in patients with chest pain and normal coronary arteriograms using a specific questionnaire. Clin Cardiol 1999; 22, 283-290. • JC Kaski et al. Cardiac syndrome X. Diagnosis, pathogenesis and management. Am J Cardiovasc Drugs 2004; 4: 179-94. • F Crea, GA Lanza. Angina pectoris and normal coronary arteries: cardiac syndrome X. Heart 2004; 90: 457–463.

  7. Psychological Burden CSX patients had elevated neuroticism scores and a high degree of anxiety that correlated with increased transient ST segment changes on Holter. Ruggeri A et al. The correlation between the clinical characteristics and psychological status in CSX patients. Cardiologia. 1996 Psychosocial problems are a consequence of CSX and not the cause. Zachariae R et al. Experimental pain and psychologic status of patients with chest pain with normal coronary arteries or ischemic heart disease. Am. Heart J. 2001 High neuroticism scores among patients with anginal symptoms and restricted physical activity. Lantinga LJ et al. One-year psychosocial follow-up of patients with chest pain and angiographically normal coronary arteries. Am. J. Cardiol. 1988 Anxiety, depression, and panic disorders are common in CSX. Potts SG, Bass CM. Psychological morbidity in patients with chest pain and normal or near-normal coronary arteries: a long-term follow-up study. Psychol. Med. 1995

  8. Psychosocial Morbidity in Women with Cardiac Syndrome X 100 CSX (60±9 years), 100 CHD (65±9 years) and 100 healthy subjects (61±10 years) completed the hospital anxiety and depression scale (HADS), health anxiety questionn. (HAQ), demographics & life events scales, and menstrual, menopausal and gynaecological questionnaires Women with cardiac syndrome X had more psychological morbidity compared to CHD patients and controls Life events and social network size were related to health anxiety, general anxiety and depression Asbury E et al. Eur Heart J 2004

  9. Coronary Microvascular Dysfunction in Angina Pectoris Functional and structural mechanisms can lead to coronary microvascular dysfunction (CMD) in subjects with angina but without CAD (Cardiac syndrome X) Structural Coronary Microvascular Dysfunction Functional Coronary Microascular Dysfunction

  10. Coronary Microvascular Dysfunction in Patients with Cardiac Syndrome X Functional microvascular abnormalities • Oestrogen deficiency (menopausal) • Endothelial dysfunction Risk factors Subangiographic atheroma Endothelin-1 release Inflammation / Oxidative stress

  11. Plaque vulnerability Inflammation Thrombosis Vasoconstriction Endothelial Activation and Atherogenesis Dyslipidaemia Obesity Systemic inflammatory conditions Inflammation Oxidative Stress Smoking Hypertension Diabetes and Metabolic Syndrome Endothelial Activation / Dysfunction ↓NO ↑ET-1 ↑Ang II ↑NFkB Macrophage activation T-cell recruitment ↑ MMP-9 ↑ CAMs – ↑ MCP-1 Cytokines – E-selectin - TNFa-IFNg– CD40L ↑ PAI-1 ↑ Platelet adhesion ↓NO/ET-1

  12. Coronary Endothelial Dysfunction and Prognosis Cardiac events (%) G1 G2 G3 P<0.05 16 12 8 4 0 • Al Suwaidi J et al. Long-term follow-up of patients with mild CAD and coronary endothelial dysfunction. Circulation. 2000 • Halcox JPJ et al. Prognostic value of coronary and systemic endothelial function in CAD & non CAD patients. Circulation 2002 and Circulation 2009 • Bugiardini R et al.Predictive role of endothelial dysfunction in women with “de novo” angina and angiographically normal coronary arteries. Circulation. 2004 P<0.01 IMT Progression FMD QUARTILE

  13. FMD and Prognosis In the nested case-cohort Multi-Ethnic Study of Atherosclerosis (n=2843 individuals free of CV disease and 182 cases), an abnormal baseline brachial artery FMD was inversely predictive of incident CV events at 5 years. FMD however did not provide incremental discrimination to the Framingham risk score 100 90 80 FMD ≥ median Percent survival FMD < median Log rank p<0.0001 = 0 500 1000 1500 Time to CV events/last f up (days) Cumulative event-free survival stratified by FMD ≥ or < the sex-specific median value for the cohort Yeboah, J, Folsom, AR, Burke, GL, et al. Circulation 2009; 120:502

  14. Implications for Patient Management

  15. Heterogeneity!

  16. Management of Cardiac Syndrome X TARGETS • Endothelial and coronary microvascular dysfunction • Myocardial ischaemia • Pain perception abnormalities • Psychological disturbances

  17. Management of Cardiac Syndrome X GOALS • Abolish myocardial ischaemia • Improve pain perception • Improve quality of life (i.e. functional status, anxiety, return to work)

  18. Mrs. S.X. Clinical case 55 years – Post menopausal “White coat” hypertension Hypercholesterolaemia Chest pain on mild exertion Positive ETT (ST segment depression and chest pain) Anxiety Normal coronary angiogram Cardiology Unit Dear Dr ………………. Thank you for asking me to see this patient with a longstanding history of chest pain despite normal coronary arteries. Without a doubt some of her symptoms (i.e. prolonged exertional and rest chest pains) are medically unexplainable. …should she develop further symptoms which can be definitely associated with ischaemia or arrhythmia I would be happy to see her again. I have reassured her that there is no serious heart disease.

  19. Dear GP Re: Mrs S.X – DOB: 1-11-50 , 321 Any Rd, London SW17 Diagnosis: Chest pain on exertion, normal coronary angiogram, ?Syndrome X Without a doubt some of her symptoms (i.e. prolonged exertional chest pains) are medically unexplainable in the absence of angiographic coronary artery disease. ….. also the diagnosis of Syndrome X is what I might call a dustbin diagnosis in that the evidence for it can rarely be elicited. I have reassured her that there is no serious heart disease and she should return to work …should she develop further symptoms, which can be associated with ischaemia or arrhythmia I would be happy to see her again. Dr. ……… Consultant Cardiologist

  20. 24 kg/m2 118/68 1.8 mmol/L 5.2% NA No subendoc ischaemia ACEI, STATINS, CCB, VASODILATORS, DIET, EXERCISE PROGRAMME MICROVASCULAR ANGINA Mrs S.X. after treatment Mrs. S.X. Diagnostic Importance BMI 31 kg/m2 BP 148/90 (on average) LDL-C 4.8 mmol/L FMD 1.2% CFR (PET) 1.8 MRI: subendocardial ischaemia

  21. ACE inhibition reduces plasma asymmetric dimethylarginine (ADMA) and improves endothelial NO bioavailability and coronary microvascular function. JW Chen et al. Am J Cardiol 2002 P=.002 P=.766 Endothelial Dysfunction as a Therapeutic Target in Cardiac Syndrome X ACE inhibition improves microvascular dysfunction and ETT responses in CSX patients. JCKaski et al. JACC 1994

  22. Statin therapy improves FMD and exercise induced ischaemia Kayikcioglu et al. EHJ 2003 Fabian et al. Am J Cardiol 2004 Beneficial Effects of “Anti-inflammatory” Interventions in Cardiac Syndrome X Treatment with ramipril & atorvastatin improves endothelial function via reduced oxidative stressPizzi et al. Circulation 2004

  23. Effects of metformin on microvascular function and exercise tolerance in women with angina and normal coronary arteries 8-week double-blind, randomized, placebo-controlled study of metformin 500 mg bd in 33 nondiabetic women with normal coronary angiography but two consecutive positive (ST-depression > 1 mm) exercise tolerance tests Chest Pain Maximal ST-Segment Depression Jadhav S et al. J Am Coll Cardiol 2006;48:956–63

  24. Microvascular dysfunction (estrogen deficiency, diabetes, metabolic syndrome, risk factors, endothelial dysfunction, inflammation) Ischemia Calcium channel antagonists B-blockers Nitrates Risk factor reduction ?HRT, aggressive risk factor reduction, ACEi, statins Specific treatment Chest Pain and Normal Coronary Angiogram Extracardiac causes (Esophageal, musculo-skeletal, psychological, chronic fatigue syndrome) • Coronary spasm, • amyloidosis, LVH, other secondary causes Increased pain sensitivity Imipramine Aminophylline, TENS, SCS, referral to pain unit JC Kaski - Circulation 2004

  25. Thank you

  26. Investigate: Myocardial ischaemia & other cardiac mechanisms Extracardiac causes Psychological status Negative findings Positive findings Reassurance Treat as appropriate Risk factor management Lifestyle changes Improved symptoms Physical training Symptomatic Focus on management of pain Follow-up

  27. Bill Costs associated with patient characterization(£) Initial assessment .……..£3,000 (Euros 3,450) Admission……………… £3,000 (Euros 3,450) Repeat tests……………...£2,500 (Euros 2,875) Total £……………………..£8,500 (Euros 10,000) Burden to Health Service

  28. Effects of metformin on microvascular function and exercise tolerance in women with angina and normal coronary arteries Blood Flow Response 8-week double-blind, randomized, placebo-controlled study of metformin 500 mg bd in 33 nondiabetic women with normal coronary angiography but two consecutive positive (ST-depression > 1 mm) exercise tolerance tests Jadhav S et al. J Am Coll Cardiol 2006;48:956–63

  29. Angina with “normal” coronary arteries: Gender differences in outcomes Retrospective cohort study using prospectively collected angiographic and clinical data on all patients in British Columbia, Canada (n= 32,856) presenting for their first cardiac catheterization with suspected IHD but angiographically normal coronaries (7% men versus 23% women) (P < .001) Clinical differences between men and women at baseline: Women were older and more likely to present with hypertension, prior stroke, COPD and PVD Clinical Outcome at 1 year: 1.0% died, (19 women, 18 men, P = .27) and 0.6% had a stroke (13 women, 9 men, P = .91). Readmission to hospital for ACS was higher in women (adjusted OR 4.06; 95% CI 1.15-14.31). K H. Humphries et al. Am Heart J 2008;155:375-381

  30. Angina with “normal” coronary arteries: Gender differences in outcomes CONCLUSIONS In a contemporary, population-based cohort presenting for cardiac catheterization for suspected ischemia, women with angiographically normal coronaries were >4 times more likely to be readmitted to hospital for ACS/chest pain within 180 days compared to men The observed sex difference has important social and economic implications and suggests that traditional diagnostic methods may not be optimal for women K H. Humphries et al. Am Heart J 2008;155:375-381

  31. 1 0.8 0.6 0.4 0.2 0 Brachial FMD Framingham Risk Score FRS + FMD SENSITIVITY 0.2 0.4 0.6 0 0.8 1.0 1-SPECIFICITY FMD and Prognosis In the nested case-cohort Multi-Ethnic Study of Atherosclerosis (n=2843 individuals free of CV disease and 182 cases) brachial FMD did not provide incremental discrimination to the Framingham risk score as assessed by the C-statistic Receiver operating characteristic curves for FRS (AUC 0.74), brachial FMD (AUC 0.65), and FRS + FMD (AUC 0.74) to predict incident CVD events Yeboah, J, Folsom, AR, Burke, GL, et al. Circulation 2009; 120:502

  32. CSX - Determinants of Risk CAD risk factors and gender Endothelial dysfunction “Occult” CAD Myocardial ischaemia LVH – DCM – LBBB Chronic inflammation Primary diseases (i.e. amyloid) Pain perception abnormalities Low High Risk of events

  33. Early Atherosclerosis in Rheumatic Disease: Inflammation and Microvascular Dysfunction Hypothesis In the absence of conventional CV risk factors, chronic inflammation could result in coronary microvascular dysfunction - Microvascular dysfunction can cause angina pectoris (microvascular angina) Recio A, Mason JC, Kaski JC, Rubens MB, Harari OA, Camici PG. Eur Heart J 2009;30:1837

  34. 12 Patients with RA & 13 with SLE Age under 55 years No history of hypertension, hyperlipidaemia, diabetes, smoking, coronary disease or other CV disease. No statin treatment Coronary artery disease: “Occult” coronary stenosis ruled out by 64-slice CT angiography and/or conventional coronary angiography 25 age and gender matched controls Patients and Controls Recio A, Mason JC, Kaski JC, Rubens MB, Harari OA, Camici PG. Eur Heart J 2009;30:1837

  35. ·O2- O2 Nox2 (gp91phox) p22phox Rac p67phox p47phox p40phox NADP+ NADPH ROS Production and Vascular Dysfunction Increased ROS reduces bioactive NO through chemical inactivation, forming toxic peroxynitrite, which can uncouple eNOS to form a dysfunctional superoxide-generating enzyme that contributes further to oxidative stress Dysfunctional eNOS Xanthine Oxidase ROS NADPH Oxidase Mitochondrial Respiratory Chain Multicomponent membrane enzymes in ECs, VSMCs and fibroblasts Several enzymes/enzyme systems in the vessel wall can produce ROS PHAGOCYTIC CELLS San José et al. Clin Sci 2008;114:173-182 Mueller CF et al. ATVB 2005; 25: 274–278

  36. Prognosis in Patients with Chest Pain and Normal Coronary Angiograms Clinical presentation Stable angina Acute Coronary Syndrome

  37. Prognosis in CSX - Determinants of Risk CAD risk factors Endothelial dysfunction “Occult” CAD Myocardial ischaemia LVH – DCM – LBBB Chronic inflammation Primary diseases (i.e. amyloid) Low High Risk of CAD and events

  38. Cardiac Syndrome X • Typical exertional/rest chest pain • Ischaemic ECG changes • Normal coronary arteriograms JC Kaski et al. Am J Cardiol. 1986 Long-term prognosis is good in patients with cardiac Syndrome X JC Kaski et al.Cardiac syndrome X: clinical characteristics. Long term follow up study. J Am Coll Cardiol. 1995;25:807-14.

  39. Long-term outcome in patients with angina-like chest pain and normal coronary angiograms Scholz M et alHerz. 2003; 28:413-20 PATIENTS: 185 consecutive patients (age 54 ±7.8 y, 59% male) with typical angina and completely normal coronary arteries and LV function - 72 patients had myocardial ischaemia during pain (ECG, 51; scintigraphy, 21) RESULTS - Follow up: 12.0 ±2.9 years Fatal AMI: 1 (0.05% per year) - Non-fatal MI: 0 ?Cardiac death: 9 patients (0.51% per year) Significant CAD: 6 (0.3% per year) CONCLUSION: CSX patients have good long-term prognosis similar to that in the general population

  40. Angina Pectoris and Normal Coronary Arteries: Prognosis in Men and Women Compared tothe General Population Oerlemans J G et al. Nederlands tijdschrift voor geneeskunde 2000;144(11):522-7 • METHODS: Medline (1966 -1998) and De geïnformeerde huisarts (1992-1998) search. Data on prognosis in the general population obtained from WHO • RESULTS: In patients with suspected angina pectoris and angiographically normal coronary arteries: • Deaths per 1000 pt/yrs: 0 to 6.59 (mean: 4.05) • Cardiac deaths (CAD): 0 to 0.92 (0.47) • Non fatal MIs: 0 to 1.83 (0.94) • These figures were similar to those in the general population • CONCLUSION: Prognosis (mortality and non fatal MI) in patients with angina pectoris and normal coronary arteries is similar to that in the general population

  41. Prognosis in patients with unstable angina and nonobstructive atherosclerotic coronary artery disease R Bugiardini, C. N Bairey Merz. JAMA 2005 MEDLINE and Cochrane Database of Systematic Reviews searches showed that prognosis is not benign in patients with unstable angina and nonobstructive atherosclerotic coronary artery disease and includes a 2% risk of death or myocardial infarction at 30 days of follow-up At least 20% of women with normal or nonobstructive angiography have myocardial ischemia, likely due to endothelial dysfunction, which itself is associated with an increased risk of adverse cardiac events and the development of obstructive CAD

  42. CSX- Prognosis in the ACS setting Limitations of current studies: • Retrospective nature – Literature review • Patients with ACS differ from stable angina patients (CSX) reported in previous articles on chest pain with normal findings on angiography • ACS carries a long-term increased risk of recurrence, irrespective of coronary anatomy • Patients with “near-normal” angiograms included – Lack of IVUS data • Use of prognostic markers other than clinical scores (i.e. FMD/endothelial function)?

  43. Heterogeneous Pathogenesis in Patients with Chest Pain and Normal Coronary Angiograms Implications regarding prognosis and management Heterogeneous population Co-morbidities Assessed by different diagnostic tools (limitations) Prognosis depends on multiple variables

  44. Early Atherosclerosis in Rheumatic Disease: Inflammation and Microvascular Dysfunction Among patients with cardiac syndrome X are young individuals with chronic inflammatory conditions i.e. Rheumatoid Arthritis (RA) and Systemic Lupus Erythematosus (SLE) RA and SLE patients have an increased risk of cardiovascular events compared to the general population

  45. p < 0.0001 MyocardialPerfusion (ml.min-1.g-1) Basal Adenosine Basal Adenosine Patients Controls Myocardial Perfusion- Individual Responses

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