1. Il tribunale del cardiologo: Processo allo studio della riserva coronarica Avvocato difensore Lauro Cortigiani U.O. Malattie Cardiovascolari Ospedale Campo di Marte, Lucca CARDIOLOGIA E PROGRESSOCARDIOLOGIA E PROGRESSO II° Congresso Tosco-Umbro della FIC Montecatini terme, 14-15 novembre 2007 CardioLucca

2. Coronary blood flow Coronary stenosis % 0 0 1 2 3 4 20 40 6080 100 Basal flow Basal flow Maximal flow Maximal flow Effects of coronary stenosis on CFR Gould. Am J Cardiol 1974;34:48 CardioLucca

3. CFR>2(86%) CFR<2 (30%) (30%) Subjects at risk CFR>2 CFR>2 39 21 12 5 CFR<2 CFR<2 47 22 6 2 0122436 0 20 40 60 80 100 Time (months) Spontaneous event-free survival (%) n = 86 p = 0.0001 Prognostic effect of CFR in patients with 51% to 75% stenosis of the LAD Rigo, for the EPIC-FR. Am J Cardiol 2007;100:1527 CardioLucca Infarction-free survival %

4. Correlation between CFR and LAD stenosis EPIC-FR 2007 CardioLucca n = 1,243 r = 0.53 p < 0.0001 n = 1,243 n = 1,243 r = - 0.53 r = - 0.53 p < 0.0001 p < 0.0001

5. Factors affecting the functional significance of coronary artery stenosis Percent diameter stenosis Percent diameter stenosis Geometry and lenght of the lesion Geometry and lenght of the lesion Minimum diameter and cross-sectional area of the lesion Minimum diameter and cross-sectional area of the lesion Size of the vessel proximal and distal to the lesion Size of the vessel proximal and distal to the lesion Vasoactivity of the lesion Vasoactivity of the lesion Viable or necrotic state of myocardium Viable or necrotic state of myocardium Degree of distal collateral support Degree of distal collateral support Left ventricular hypertrophy Left ventricular hypertrophy Microvascular disease Microvascular disease Folland. Circulation 1994;89:2005(modified) CardioLucca

6. Sekiya. Am J Hypertens 2000;13:789 Relation between LV mass and CFR Rigo, Cortigiani. Eur Heart J 2006;27(abs) Intracoronary Doppler Transthoracic Doppler r = 0.85 p < 0.01 % increase of CBF with ACh LV mass index (g/m 2 ) 406080100120140160180 50 100 150 200 250 300 350 400 CardioLucca LV mass index (g/m 2 ) CFR on LAD r = - 0.85 p < 0.01 r = - 0.57 p < 0.0001

7. Transthoracic Doppler of mid-distal LAD Modified apical 3-chambers CardioLucca

8. Techniques of assessing CFR Mesaurement of flow Radiation exposure CostAvailabilityAccuracy PETAbsolute+++ Very high -+++ Intracoronary Doppler Relative+++High++++ Magnetic resonance Relative-High++++ Transesophageal Doppler Relative-Low++++ Transthoracic Doppler Relative- Very low +++++ Picano. Stress Echocardiography. 4th ed, 2003 CardioLucca

9. Comparison of CFR on LAD by transthoracic Doppler and intracoronary Doppler flow wire Caiati. Circulation 1999;99:771 CardioLucca Mean + 2SD Mean - 2SD Mean R = 0.88 R = 0.88

10. CFR profile with transthoracic Doppler Hyperemic Resting diastolic velocity SystoleDiastole Velocity(cm/sec) Velocity(cm/sec) Resting Hyperemic CardioLucca CFR =

11. 6832 =2.13 RestingHyperemic CardioLucca

12. Hozumi JACC 1998 Caiati JACC 1999 Pizzuto AJC 2003 Nohtomi JASE 2003 Ruscazio JACC 2003 Rigo AJC 2003 Cortigiani JACC 2007 Feasibility of transthoracic Doppler of LAD CardioLucca % n=1544n=230n=110n=53n=45n=138n=18

13. Hozumi JACC 1998 Caiati JACC 1999 Pizzuto AJC 2003 Nohtomi JASE 2003 Ruscazio JACC 2003 Rigo AJC 2003 EPIC-FR 2007 % n=1243n=230n=110n=53n=45n=138n=18 Diagnostic value of CFR for LAD disease SensitivitySpecificity CardioLucca

14. % SensitivitySpecificityAccuracy Normotensives (n = 396) Hypertensives (n = 847) p = 0.06 p = 0.40 p = 0.28 Accuracy of CFR 70% LAD stenosis in normotensives and hypertensives CardioLucca EPIC-FR 2007

15. Better value of CFR to assess >70% LAD stenosis 2.00 1.92 EPIC-FR 2007 CardioLucca 1.92 1.97 AUC = 0.90 (0.88-0.92) Sensitivity = 89% Specificity = 82% AUC = 0.89 (0.85-0.91) Sensitivity = 88% Specificity = 79% 396 Normotensives 847 Hypertensives

16. % 1-2 vessel (n = 248) Frequency of reduced CFR on LAD in pts with RCA or LCx disease and <70% LAD stenosis 0-vessel (n = 720) n = 968 p = 0.15 EPIC-FR 2007 CardioLucca

17. CardioLucca Transthoracic Doppler of RCA Modified apical 2-chambers

18. Rigo CU 2005 Takeuchi JASE 2004 Voci AJC 2002 % n=151n=446n=81 Feasibility and diagnostic value of CFR for RCA disease SensitivitySpecificity Rigo CU 2005 Takeuchi JASE 2004 Voci AJC 2002 % n=151n=446n=81 Feasibility CardioLucca

19. Limitations of CFR as stand-alone diagnostic criterion CardioLucca Only LAD is sampled Only LAD is sampled Inability to distinguish between Inability to distinguish between macrovascular and microvascular CAD macrovascular and microvascular CAD Only LAD is sampled Only LAD is sampled Inability to distinguish between Inability to distinguish between macrovascular and microvascular CAD macrovascular and microvascular CAD

20. Dip 2D + CFR CFR on LAD adds diagnostic value over wall motion analysis during dipyridamole stress echo CardioLucca 5 studies 741 pts Sensitivity Sensitivity Specificity Specificity Accuracy Accuracy % Dip 2D Rigo. J Cardiovasc Med 2006;7:472

21. CardioLucca Mestre Rigo Cesena Gherardi Pisa Sicari, Picano Lucca Cortigiani Napoli Galderisi Empoli Gianfaldoni Belgrade Djordjevic-Dikic EPIC-FR: Recruiting Centers 2007 CardioLucca

22. 06 10 min Dipyridamole 0.84 mg/kg in 6 0.84 mg/kg in 6 TIMELINE 1 lead ECG 12 lead ECG BP recording Drugs infusion Aminophylline 120 mg in 1 (up to 240 mg in 2) 120 mg in 1 (up to 240 mg in 2) CFR-PW 2D echo Continuous monitoring and Pulsed recording Continuous monitoring and Pulsed recording On the echo-monitor Dipyridamole stress echo with CFR assessment CardioLucca

23. 01224 0 20 40 60 80 100 Months Event-free survival (%) 618 CFR >2 / DET – CFR <2 / DET – CFR >2 / DET + CFR <2 / DET + n = 1,145 p < 0.0001 CardioLucca Incremental prognostic value of CFR over wall motion analysis Rigo, for the EPIC-FR. Eur Heart J 2008;(in press)

24. Annual hard event rate (%) Suspected CAD Suspected CAD Known CAD 6.0 8.5 4.7 2.2 Nondiabetics NondiabeticsDiabetics Annual hard event rate in diabetics and nondiabetics 5,456 pts Cortigiani. JACC 2006;47:605 CardioLucca

25. Prognostic value of stress echo result n = 749 p < 0.0001 n = 4,707 p < 0.0001 Cortigiani. JACC 2006;47:605 CardioLucca Diabetics Nondiabetics n = 4,707 p < 0.0001 n = 749 p < 0.0001

26. Prognostic value of CFR in diabetics and nondiabetics with no inducible ischemia Diabetics Nondiabetics CardioLucca Cortigiani, for the EPIC-FR. JACC 2007;50:1354

27. Anti-ischemic therapy negatively affects the prognostic value of stress echo SE- / On therapy (88%) SE+ / Off therapy (84%) SE+ / On therapy (81%) SE- / Off therapy (95%) Time (months) Total mortality (%) CardioLucca Sicari, Cortigiani, Picano. Circulation 2004;109:2428 n = 7,333

28. n = 1,506 p < 0.0001 Time (months) Infarction-free survival (%) CFR <2 - On Therapy (74%) CFR <2 - On Therapy (74%) CFR <2 - Off Therapy (79%) CFR >2 - Off Therapy (93%) CFR >2 - On Therapy (91%) CFR>2 - On Therapy CFR>2 - On Therapy 369 260 135 54 10 CFR<2 - Off Therapy CFR<2 - Off Therapy 262 108 57 24 7 CFR>2 - Off Therapy CFR>2 - Off Therapy 586 369 186 87 27 CFR<2 - On Therapy CFR<2 - On Therapy 289 105 40 16 2 Subjects at risk 0 12 24 36 48 Sicari, for the EPIC-FR. Submitted CardioLucca Anti-ischemic therapy does not affect the prognostic value of CFR

29. Characteristics of 1.243 patients CFR > 2 (n = 725) CFR < 2 (n = 514) p value Age Age62±1165±10<0.0001 Men Men63%63%0.85 Prior infarction Prior infarction34%39%0.06 Prior PCI Prior PCI35%30%0.06 Family history of CAD Family history of CAD24%26%0.39 Diabetes Diabetes20%26%0.02 Hypercholesterolemia Hypercholesterolemia62%71%0.0006 Hypertension Hypertension65%73%0.003 Smoking habit Smoking habit35%37%0.49 Resting LVEF Resting LVEF55±752±9<0.0001 Ischemia on SE Ischemia on SE19%53%<0.0001 CFR CFR2.63±0.541.70±0.25<0.0001 2-3 vessel 2-3 vessel6%31%<0.0001 1 vessel 1 vessel21%33%<0.0001 0 vessel 0 vessel73%36%<0.0001 EPIC-FR 2007 CardioLucca

30. Multivariable prognostic indicators (death, STEMI, NSTEMI) HR (95% CI) p value p value Ischemia at stress echo Ischemia at stress echo 3.37 (2.43-4.68) < 0.0001 CFR <2.0 CFR <2.0 2.82 (2.12-4.57) < 0.0001 CAD at angiography CAD at angiography 2.34 (1.68-3.26) < 0.0001 Hypertension Hypertension 1.64 (1.21-2.40) 0.002 CardioLucca EPIC-FR 2007

31. Clinical ClinicalLVEF ClinicalLVEFAngio ClinicalLVEFAngioSE ClinicalLVEFAngioSECFR + 14% + 279% + 46% + 13% Incremental prognostic value of CFR EPIC-FR 2007 CardioLucca

32. Clinical ClinicalLVEF ClinicalLVEFSE ClinicalLVEFSECFR ClinicalLVEFSECFRAngio + 14% + 394% + 25% + 2% Incremental prognostic value of CFR EPIC-FR 2007 CardioLucca

33. Prognostic value of CFR in pts with and without significant (>70% stenosis) CAD EPIC-FR 2007 CardioLucca No significant CAD Significant CAD n = 523 p = 0.0007 n = 720 p < 0.0001 327

34. CardioLucca EPIC-FR 2007 Prognostic implication of CFR assessed on LAD and RCA n = 553 p < 0.0001

35. LAD (-) RCA (-) LAD (+) RCA (-) LAD (-) RCA (+) LAD (+) RCA (+) Frequency of significant CAD according to CFR assessed on LAD and RCA CardioLucca EPIC-FR 2007 553 pts Significant CAD %

36. Prognostic value of CFR in dilated cardiomyopathy Rigo, for the EPIC-FR. Eur Heart J 2006;27:1319 CFR<2 (22%) CFR>2 (70%) CFR<2 CardioLucca n=129p=0.0001 CFR>2 CFR<2 Subjects at risk

37. Prognostic value of PET derived CFR in HCM Cecchi. NEJM 2003;349:1027 CardioLucca

38. Doppler echocardiographic derived CFR in HCM 68 HCM patients (58 12 yy; 59% men) 68 HCM patients (58 12 yy; 59% men) NYHA class I-II NYHA class I-II Angiographically normal coronary Angiographically normal coronary arteries (n=37) or negativity of stress arteries (n=37) or negativity of stress test and likelihood of CAD <5% (n=31) test and likelihood of CAD <5% (n=31) High-dose dipyridamole (0.84 mg High-dose dipyridamole (0.84 mg over 6) with CFR assessment of LAD over 6) with CFR assessment of LAD Follow-up: 22 13 months Follow-up: 22 13 months CardioLucca Cortigiani, for the EPIC-FR. Submitted

39. Follow-up events 1 sudden death 1 AMI 4 ICD 6 hospitalizations for heart failure (4 of whom for pulmonary edema) (4 of whom for pulmonary edema) 5 unstable anginas 8 atrial fibrillations 2 syncope 27 events CardioLucca Cortigiani, for the EPIC-FR. Submitted

40. Univariate analysis (HR, 95% CI) p value p value Multivariate analysis (HR, 95% CI) p value p value Age Age 1.00 (0.99-1.03) 0.81 Men Men 1.25 (0.57-2.75) 0.57 Angina Angina 3.50 (1.62-7.58) 0.001 2.53 (1.11-5.74) 0.03 NYHA II NYHA II 4.86 (2.25-10.48) <0.0001 Syncope Syncope 3.54 (1.51-8.30) 0.004 Paroxysmal or chronic AF Paroxysmal or chronic AF 2.24 (1.00-5.01) 0.05 NSVT NSVT 2.11 (0.92-4.84) 0.08 LBBB on ECG LBBB on ECG 1.16 (0.49-2.75) 0.73 Left atrial dimension Left atrial dimension 1.18 (1.04-1.33) 0.008 LV end-diastolic dimension LV end-diastolic dimension 1.00 (0.93-1.07) 0.95 EF% EF% 0.94 (0.87-1.02) 0.14 Maximal LV thickness Maximal LV thickness 1.19 (1.08-1.30) <0.0001 Rest LV obstruction (>30 mmHg) Rest LV obstruction (>30 mmHg) 6.52 (2.93-14.51) <0.0001 2.70 (1.14-6.39) 0.02 Moderate to severe mitral regurg. Moderate to severe mitral regurg. 2.96 (1.23-7.12) 0.01 CFR <2 CFR <2 7.61 (2.61-22.16) <0.0001 4.30 (1.34-13.78) 0.01 ECG changes ECG changes 2.38 (0.93-6.08) 0.07 Cox analysis Cortigiani, for the EPIC-FR. Submitted

41. Event-rates according to CFR CardioLucca CFR >2 (79%) CFR <2 (17%) CFR >2 n = 68 p < 0.0001 Cortigiani, for the EPIC-FR. Submitted

42. Functional aspects of coronary circulation Ischemia CFR CardioLucca

43. Conclusions CFR evaluation of LAD by transthoracic Doppler: is highly feasible (>90%); is highly feasible (>90%); increases the sensitivity of dipyridamole stress echo with only modest loss in specificity; increases the sensitivity of dipyridamole stress echo with only modest loss in specificity; provides strong and independent prognostic information in patients with known or suspected CAD (including diabetics), additional to that of wall motion analysis and angiographic findings; provides strong and independent prognostic information in patients with known or suspected CAD (including diabetics), additional to that of wall motion analysis and angiographic findings; if effective to risk stratify patients with dilated and hypertrophic cardiomyopathy. if effective to risk stratify patients with dilated and hypertrophic cardiomyopathy.

44. Microvasculardisease Normal Moderate- to-severe CAD Wall motion Mild-to- Moderate CAD CFR STRESS Coronaryangiography Prognosticimpact ± - + + + Coronary anatomic and prognostic CFR conditions CardioLucca Cortigiani, for the EPIC-FR. JACC 2007;50:1354

45. Diagnostic value of CFR for LAD disease N° pts FeasibilitySensitivitySpecificityAccuracy Hozumi JACC 1998 1878%94%100%98% Caiati JACC 1999 13888%88%76%87% Pizzuto Am J Cardiol 2003 4596%97%91%93% Ruscazio JACC 2003 5397%78%93%80% Nohotomi JASE 2003 11092%94%65%81% Rigo Am J Cardiol 2003 23094%81%84%83% EPIC-FR 2007 1,24392%91%73%77% CardioLucca

46. N° pts FeasibilitySensitivitySpecificityAccuracy Voci Am J Cardiol 2002 8154%89%96%- Takeuchi JASE 2004 15183%91%75%83% Rigo Cardiovasc Ultras 2005 44668%89%72%81% CardioLucca Diagnostic value of CFR for RCA disease

47. REST EXE DOBU ADO DIPY CFR and stresses Iskandrian. J Nucl Cardiol 1994:1;94 X X X X X CFR CardioLucca

48. CFR with vasodilator agents AdenosineDipyridamole Patient tolerance LowerHigher Drug cost 100 Euros 1 Euro HyperventilationHigherLower Vasodilator effect onset Seconds (30) Minutes (2-3) Combined wall motion and CFR DifficultPossible Multiple coronary imaging DifficultPossible Picano. Stress Echocardiography. 4th ed, 2003 CardioLucca

49. Patients CFR > 2 (n=37) CFR < 2 (n=31) p value Age Age59±1257±110.59 Men Men65%52%0.27 Angina Angina14%45%0.004 NYHA class NYHA class1.3±0.41.4±0.50.22 Syncope Syncope3%29%0.02 Paroxysmal or chronic AF Paroxysmal or chronic AF14%35%0.03 NSVT NSVT13%23%0.19 LBBB on ECG LBBB on ECG24%26%0.89 Left atrial dimension (mm) Left atrial dimension (mm)42±445±40.02 LV end-diastolic dimension (mm) LV end-diastolic dimension (mm)50±550±50.92 LV end-sistolic dimension (mm) LV end-sistolic dimension (mm)30±531±60.57 EF% EF%58±559±60.30 Maximal LV thickness (mm) Maximal LV thickness (mm)17±320±4<0.0001 Rest LV obstruction (>30 mmHg) Rest LV obstruction (>30 mmHg)5%55%<0.0001 Moderate to severe mitral regurg. Moderate to severe mitral regurg.8%23%0.09 CFR on LAD CFR on LAD2.2±0.41.8±0.1<0.0001 ECG changes ECG changes30%42% 0.29 0.29 CardioLucca Cortigiani, for the EPIC-FR. Submitted

50. Causes of reduced CFR in dilated cardiomyopathy LV hypertrophy Increased LV end-diastolic pressure Coronary small vessel disease LV hypertrophy Increased LV end-diastolic pressure Coronary small vessel disease CardioLucca