Disclosures Department of Cardiac Sciences and Libin Cardiovascular - - PowerPoint PPT Presentation

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

R1 R2 R3

P1 P2

PLV

Nitric Oxide PGI2 EDHF Vasodilation Antiinflammatory Antiplatelet Fibrinolysis Antiproliferative Endothelin Ang II Free radicals TxA2 Vasoconstriction Inflammation Platelet aggregation Procoagulant Proliferative Disease Health

Vascular Homeostasis

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

Ong et al. JACC, 2008;52:523

488 pts with ACS 138 (28%) no culprit 86 received Ach 100 mcg left 80 mcg right 49% had >75% constriction

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-
• bstructive 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

Buchtal et al. NEJM 2000;342:829

Handgrip exercise 20% of chest pain and no CAD have decrease in ratio suggestive of ischemia

Abnormal Cardiac Adrenergic Function

Di Monaco 2010;106:1813

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

Chest pain and normal CA – MS in WISE population

Kip et al. Circ 2004;107:706

60% MS, 40% CAD

Chest pain and normal CA- Diagnosis

Bugiardini et al. JAMA 2005;293:477

Proposed scheme for investigation

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

Shaw et al. JACC 2006;47:36S

Duke Activity Score index – DASI Not ETT WISE cohort N=913

Chest pain and normal CA- Prognosis

von Mering et al. Circulation 2004;209:722

163 WISE Referred for angio for CP No CFR relationship Ach related to

• utcomes

58 events

With event - -8% change CSA No event – +8% change CSA

Chest pain and normal CA- Prognosis

Pepine et al. JACC 2010;55:2825

189 WISE Referred for angio for CP 152 without CAD CFR <2.3 predictive of AE

Chest pain and normal coronary arteries

Johnson et al. EHJ 2006;27:1408

673 women in WISE study Persistent CP in women with no CAD Predicts adverse outcomes

Excluded 4 Females Subjects with events

• 36 subjects with 1 events
• 30 subjects with 2 events
• 5 subjects with 3 events

Study Cohort N=1574 male firefighters N= 1578

FATE STUDY

Missing data

• VTI n=33
• FMD n=15
• IMT n=21
• FRS n= 5
• CRP n= 6

Censored events

• 18 non end-point deaths
• 15 lost or withdrew consent

Methods – Vascular End-points

FMD Hyperemic VTI

Intima Media Adventitia

Lumen

CIMT

Results – Net Clinical Reclassification Index

Clinical Reclassification Improvement I1 I2

NCRI

Z p VTI/unit SD 16.67 12.02

28.7

3.3755 <0.001 (N = 1500) Log IMT/unit SD 8.33 9.67

18.0

2.115 0.034 (N = 1512) Log CRP/unit SD 4.17 2,82

6.99

0.959 0.338 (N = 1528) VTI/unit SD 25.0 12.81

37.81

3.2907 0.002 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

Pauly et al. AJC 2011;162:678

61 WISE subjects randomized 80 mg Quinapril vs Pl CFR and SAQ EP ACE-I associated with increased CFR and decrease in angina

Ranolazine and Microvascular Angina

Mehta et al. JACC Imag 2011;4:415

Ranolazine, Placebo in a X-

• ver

20 Women Trend towards less CMR perfusion abnormality

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