Disclosures • Department of Cardiac Sciences and Libin Cardiovascular Institute – U of Calgary • No disclosures for this talk • Salary funded by AI-HS • Grant support by HSF, AI-HS • Honorarium, grant support, advisory boards – Roche, Merck, Abbott
Aims • To review the pathophysiology and prognosis of chest pain and minimal coronary artery disease
Chest pain and normal coronary arteries • More than 40% of women and 20% of men referred for coronary angiogram will have “minimal or normal coronary arteries” • Often highly symptomatic with recurrent chest pain, hospitalizations and resource utilization • Spectrum of disease with about 50% having documented ischemia • Prognosis is not as good as was once thought
Chest pain with normal coronary arteries • Recently there has been suggestion of an associated between microvascular angina and ME/CFS • High prevlance of metabolic syndrome • Some association with fibromyalga as well
Coronary disease in Women Bugiardini et al. JAMA 2005;293:477
Chest pain and normal coronary arteries • Pathophysiology • Abnormalities of vasomotion or microvascular dysfunction • Anatomical abnormalities – diffuse atherosclerosis • Metabolic abnormalities and ischemia • Altered pain perception • Metabolic syndrome
Coronary Blood Flow Anatomical R 1 P 2 R 2 P 1 R 3 P LV
Vascular Homeostasis Disease Nitric Oxide Endothelin PGI 2 Ang II EDHF Free radicals TxA 2 Health Vasoconstriction Vasodilation Inflammation Antiinflammatory Platelet aggregation Antiplatelet Procoagulant Fibrinolysis Proliferative Antiproliferative
Endothelial Dysfunction Kothawade et al. Curr Prob Cardiol 2011:36:291
Ach testing and Microvascular Angina Ong et al. JACC 2012;59:655
ACS and minimal CAD 488 pts with ACS 138 (28%) no culprit 86 received Ach 100 mcg left 80 mcg right 49% had >75% constriction Ong et al. JACC, 2008;52:523
Chest pain with normal coronary arteries • Microvascular dysfunction – CFR <2.5 – Attenuation of Ach induced increased in CBF – Chest pain, ECG change in response to Adenosine or Ach in absence of epicardial vasoconstriction – Probably overlap between Ach-induced epicardial coronary vasoconstriction and microvascular endothelial dysfunction
Abnormal coronary flow reserve • 159 women (53 years) with chest pain and non- obstructive CAD • 47% has CFR <2.5 suggestive of microvascular dysfunction • Cannot be predicted by risk factors or hormone levels • Also associated with abnormal flow-mediated dilation Reis et al. AHJ 2001;141:735 Reis et al. JACC 1999;33:1469
Ischemia by MR-spectroscopy Handgrip exercise 20% of chest pain and no CAD have decrease in ratio suggestive of ischemia Buchtal et al. NEJM 2000;342:829
Abnormal Cardiac Adrenergic Function 40 Syndrome X Abn MIBG associated with angina, repeat cath No relationship with MIBI or ETT 60% of subjects had repeat cath, 70% repeat admission Di Monaco 2010;106:1813
Chest pain and normal CA – MS in WISE population 60% MS, 40% CAD Kip et al. Circ 2004;107:706
Chest pain and normal CA- Diagnosis Proposed scheme for investigation Bugiardini et al. JAMA 2005;293:477
Chest pain and normal coronary arteries • Why is this diagnosis important? • Reasurance • Symptomatic • Resource utilization • Prognosis
Chest pain and normal coronary arteries • Resource utilization – WISE investigators have estimated lifetime cost of diagnosis and Rx of these subjects at $767 K for non-obstructive disease – 1.8 X as likely to have repeat angiography as those with 1,2,3 vessel CAD – 5 year hospitalization rates 20% – Excess of non-invasive testing and medication use compared to estabished CAD. Shaw et al. Circ 2006;114:894
Prognosis in Women- Functional Capacity Duke Activity Score index – DASI Not ETT WISE cohort N=913 Shaw et al. JACC 2006;47:36S
Chest pain and normal CA- Prognosis 163 WISE Referred for angio for CP No CFR relationship With event - -8% change CSA Ach related to No event – +8% change CSA outcomes 58 events von Mering et al. Circulation 2004;209:722
Chest pain and normal CA- Prognosis 189 WISE Referred for angio for CP 152 without CAD CFR <2.3 predictive of AE Pepine et al. JACC 2010;55:2825
Chest pain and normal coronary arteries 673 women in WISE study Persistent CP in women with no CAD Predicts adverse outcomes Johnson et al. EHJ 2006;27:1408
FATE STUDY N= 1578 Excluded 4 Females Study Cohort N=1574 male firefighters Subjects with events Censored events Missing data • 36 subjects with 1 events • 18 non end-point deaths • VTI n=33 • 30 subjects with 2 events • 15 lost or withdrew consent • FMD n=15 • 5 subjects with 3 events • IMT n=21 • FRS n= 5 • CRP n= 6
Methods – Vascular End-points Lumen Intima Media Adventitia FMD Hyperemic VTI CIMT
Results – Net Clinical Reclassification Index Clinical Reclassification Improvement I 1 I 2 Z p NCRI VTI/unit SD 16.67 12.02 3.3755 <0.001 28.7 (N = 1500) Log IMT/unit SD 8.33 9.67 2.115 0.034 18.0 (N = 1512) Log CRP/unit SD 4.17 2,82 0.959 0.338 6.99 (N = 1528) VTI/unit SD 25.0 12.81 3.2907 0.002 37.81 Log IMT/unit SD (N = 1480)
Rx of Microvascular Angina • Anti-atherosclerosis – ASA,Statins and Exercise • Specific Rx – ACE inhibition – CCB – Enhanced external counterpulation – Neurostimulation – Anti-depressants – +/- B blockers – Ranolazine – NTG Merz et al. Circ 2011;124:1477
ACE inhibition and Microvascular Angina 61 WISE subjects randomized 80 mg Quinapril vs Pl CFR and SAQ EP ACE-I associated with increased CFR and decrease in angina Pauly et al. AJC 2011;162:678
Ranolazine and Microvascular Angina Ranolazine, Placebo in a X- over 20 Women Trend towards less CMR perfusion abnormality Mehta et al. JACC Imag 2011;4:415
Chest pain and normal CA • Heterogeneous group with no clear gold standard Dx test • Prognosis not as good as previously thought • Resource utilization is very high ($750 K lifetime) • NHLBI WISE program has provided many answers since 1996 however, • Many unanswered clinical and research questions – How best to diagnose – no gold standard – Role of CMR evidence of microvascular dysfunction to be established – How best to follow for progression of CAD or abrupt events – How best to treat
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