Coronary Vasospasm as a Source of False Positive Results During Dobutamine Echocardiography

1
CARDIOLOGIA E PROGRESSO II Congresso
Tosco-Umbro della FIC Montecatini terme, 14-15
novembre 2007
Il tribunale del cardiologoProcesso allo studio
della riserva coronarica Avvocato difensore
Lauro Cortigiani U.O. Malattie
Cardiovascolari Ospedale Campo di Marte, Lucca
2
Effects of coronary stenosis on CFR
Maximal flow
4
3
Coronary blood flow
2
Basal flow
1
0
100
0
40
60
80
20
Coronary stenosis
Gould. Am J Cardiol 19743448
3
Prognostic effect of CFR in patients with
51 to 75 stenosis of the LAD
100
CFRgt2 (86)
80
60
Infarction-free survival
Spontaneous event-free survival ()
40
CFRlt2 (30)
n 86 p 0.0001
20
0
0
12
24
36
Time (months)
Subjects at risk
CFRgt2 39 21
12 5
CFRlt2 47 22
6 2
Rigo, for the EPIC-FR. Am J Cardiol 20071001527
4
Correlation between CFR and LAD stenosis
n 1,243 r 0.53 p lt 0.0001
n 1,243 r - 0.53 p lt 0.0001
EPIC-FR 2007
5
Factors affecting the functional significance
of coronary artery stenosis

• Percent diameter stenosis
• Geometry and lenght of the lesion
• Minimum diameter and cross-sectional area of
  the lesion
• Size of the vessel proximal and distal to the
  lesion
• Vasoactivity of the lesion
• Viable or necrotic state of myocardium
• Degree of distal collateral support
• Left ventricular hypertrophy
• Microvascular disease

Folland. Circulation 1994892005(modified)
6
Relation between LV mass and CFR
Intracoronary Doppler
Transthoracic Doppler
400
r 0.85 p lt 0.01
r - 0.85 p lt 0.01
r - 0.57 p lt 0.0001
350
300
250
CFR on LAD
increase of CBF with ACh
200
150
100
50
40
60
80
100
120
140
160
180
LV mass index (g/m2)
LV mass index (g/m2)
Sekiya. Am J Hypertens 200013789
Rigo, Cortigiani. Eur Heart J 200627(abs)
7
Transthoracic Doppler of mid-distal LAD
Modified apical 3-chambers
8
Techniques of assessing CFR
Mesaurement of flow Radiation exposure Cost Availability Accuracy
PET Absolute 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
9
Comparison of CFR on LAD by transthoracic Doppler
and intracoronary Doppler flow wire
R 0.88
Mean 2SD
Mean 2SD
Mean
Mean - 2SD
Caiati. Circulation 199999771
10
CFR profile with transthoracic Doppler
Systole
Diastole
Velocity (cm/sec)
Resting
Velocity (cm/sec)
Hyperemic
Hyperemic Resting diastolic velocity
CFR
11
Resting
Hyperemic
68 32
CFR

2.13
12
Feasibility of transthoracic Doppler of LAD

n1544
n230
n110
n53
n45
n138
n18
Hozumi JACC 1998
Caiati JACC 1999
Pizzuto AJC 2003
Nohtomi JASE 2003
Ruscazio JACC 2003
Rigo AJC 2003
Cortigiani JACC 2007
13
Diagnostic value of CFR for LAD disease
Sensitivity
Specificity

n1243
n230
n110
n53
n45
n138
n18
Hozumi JACC 1998
Caiati JACC 1999
Pizzuto AJC 2003
Nohtomi JASE 2003
Ruscazio JACC 2003
Rigo AJC 2003
EPIC-FR 2007
14
Accuracy of CFR lt2.0 to assess gt70 LAD stenosis
in normotensives and hypertensives
p 0.06
p 0.40
p 0.28
Normotensives (n 396)

Hypertensives (n 847)
Sensitivity
Specificity
Accuracy
EPIC-FR 2007
15
Better value of CFR to assess gt70 LAD stenosis
396 Normotensives
847 Hypertensives
1.92
1.97
2.00
2.00
1.92
AUC 0.90 (0.88-0.92) Sensitivity
89 Specificity 82
AUC 0.89 (0.85-0.91) Sensitivity
88 Specificity 79
EPIC-FR 2007
16
Frequency of reduced CFR on LAD in pts with RCA
or LCx disease and lt70 LAD stenosis
p 0.15

n 968
1-2 vessel (n 248)
0-vessel (n 720)
EPIC-FR 2007
17
Transthoracic Doppler of RCA
Modified apical 2-chambers
18
Feasibility and diagnostic value
of CFR for RCA disease
Sensitivity
Specificity
Feasibility


n151
n446
n81
n151
n446
n81
Rigo CU 2005
Takeuchi JASE 2004
Voci AJC 2002
Rigo CU 2005
Takeuchi JASE 2004
Voci AJC 2002
19
Limitations of CFR as stand-alone diagnostic
criterion

• Only LAD is sampled
• Inability to distinguish between
• macrovascular and microvascular CAD

20
CFR on LAD adds diagnostic value over wall motion
analysis during dipyridamole stress echo
Dip 2D CFR
Dip 2D


5 studies 741 pts
Sensitivity
Specificity
Accuracy
Rigo. J Cardiovasc Med 20067472
21
EPIC-FR Recruiting Centers 2007
Mestre Rigo Cesena Gherardi Pisa
Sicari, Picano Lucca Cortigiani Napoli
Galderisi Empoli Gianfaldoni Belgrade
Djordjevic-Dikic
22
Dipyridamole stress echo with CFR assessment
Dipyridamole 0.84 mg/kg in 6
Aminophylline 120 mg in 1 (up to 240 mg in 2)
Drugs infusion
0
6
min
TIMELINE
10
CFR-PW 2D echo
Continuous monitoring and Pulsed recording
1 lead ECG 12 lead ECG BP recording
On the echo-monitor
Continuous monitoring and Pulsed recording
23
Incremental prognostic value of CFR over wall
motion analysis
100
CFR gt2 / DET
80
CFR lt2 / DET
CFR gt2 / DET
60
Event-free survival ()
40
CFR lt2 / DET
n 1,145 p lt 0.0001
20
0
0
12
24
6
18
Months
Rigo, for the EPIC-FR. Eur Heart J 2008(in press)
24
Annual hard event rate in diabetics and
nondiabetics
Nondiabetics
Diabetics
8.5
Annual hard event rate ()
6.0
4.7
5,456 pts
2.2
Suspected CAD
Known CAD
Cortigiani. JACC 200647605
25
Prognostic value of stress echo result
Nondiabetics
Diabetics
n 749 p lt 0.0001
n 4,707 p lt 0.0001
n 4,707 p lt 0.0001
n 749 p lt 0.0001
Cortigiani. JACC 200647605
26
Prognostic value of CFR in diabetics and
nondiabetics with no inducible ischemia
Diabetics
Nondiabetics
Cortigiani, for the EPIC-FR. JACC 2007501354
27
Anti-ischemic therapy negatively affects
the prognostic value of stress echo
SE- / Off therapy (95)
Total mortality ()
SE- / On therapy (88)
SE / Off therapy (84)
n 7,333
SE / On therapy (81)
Time (months)
Sicari, Cortigiani, Picano. Circulation
20041092428
28
Anti-ischemic therapy does not affect
the prognostic value of CFR
CFR gt2 - Off Therapy (93)
CFR gt2 - On Therapy (91)
CFR lt2 - Off Therapy (79)
CFR lt2 - On Therapy (74)
Infarction-free survival ()
n 1,506 p lt 0.0001
0
12
24
36
48
Time (months)
Subjects at risk
CFRgt2 - Off Therapy
586 369 186 87
27
CFRgt2 - On Therapy
369 260 135 54
10
CFRlt2 - Off Therapy
262 108 57 24
7
CFRlt2 - On Therapy
289 105 40 16
2
Sicari, for the EPIC-FR. Submitted
29
Characteristics of 1.243 patients
CFR gt 2 (n 725) CFR lt 2 (n 514) p value
Age 6211 6510 lt0.0001
Men 63 63 0.85
Prior infarction 34 39 0.06
Prior PCI 35 30 0.06
Family history of CAD 24 26 0.39
Diabetes 20 26 0.02
Hypercholesterolemia 62 71 0.0006
Hypertension 65 73 0.003
Smoking habit 35 37 0.49
Resting LVEF 557 529 lt0.0001
Ischemia on SE 19 53 lt0.0001
CFR 2.630.54 1.700.25 lt0.0001
2-3 vessel 6 31 lt0.0001
1 vessel 21 33 lt0.0001
0 vessel 73 36 lt0.0001
EPIC-FR 2007
30
Multivariable prognostic indicators (death,
STEMI, NSTEMI)
HR (95 CI) p value
Ischemia at stress echo 3.37 (2.43-4.68) lt 0.0001
CFR lt2.0 2.82 (2.12-4.57) lt 0.0001
CAD at angiography 2.34 (1.68-3.26) lt 0.0001
Hypertension 1.64 (1.21-2.40) 0.002
EPIC-FR 2007
31
Incremental prognostic value of CFR
13
46
279
14
Clinical
Clinical LVEF
Clinical LVEF Angio
Clinical LVEF Angio SE
Clinical LVEF Angio SE CFR
EPIC-FR 2007
32
Incremental prognostic value of CFR
2
25
394
14
Clinical
Clinical LVEF
Clinical LVEF SE
Clinical LVEF SE CFR
Clinical LVEF SE CFR Angio
EPIC-FR 2007
33
Prognostic value of CFR in pts with and without
significant (gt70 stenosis) CAD
No significant CAD
Significant CAD
n 523 p 0.0007
n 720 p lt 0.0001
327
EPIC-FR 2007
34
Prognostic implication of CFR
assessed on LAD and RCA
n 553 p lt 0.0001
EPIC-FR 2007
35
Frequency of significant CAD according
to CFR assessed on LAD and RCA
Significant CAD
553 pts
LAD (-) RCA ()
LAD (-) RCA (-)
LAD () RCA (-)
LAD () RCA ()
EPIC-FR 2007
36
Prognostic value of CFR in dilated cardiomyopathy
CFRgt2 (70)
CFRlt2 (22)
n129 p0.0001
Subjects at risk
CFRgt2
CFRgt2
CFRlt2
CFRlt2
Rigo, for the EPIC-FR. Eur Heart J 2006271319
37
Prognostic value of PET derived CFR in HCM
Cecchi. NEJM 20033491027
38
Doppler echocardiographic derived CFR in HCM

• 68 HCM patients (58?12 yy 59 men)
• NYHA class I-II
• Angiographically normal coronary
• arteries (n37) or negativity of stress
• test and likelihood of CAD lt5 (n31)
• High-dose dipyridamole (0.84 mg
• over 6) with CFR assessment of LAD
• Follow-up 22?13 months

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) 5 unstable anginas 8 atrial
fibrillations 2 syncope
27 events
Cortigiani, for the EPIC-FR. Submitted
40
Cox analysis
Univariate analysis (HR, 95 CI) p value Multivariate analysis (HR, 95 CI) p value
Age 1.00 (0.99-1.03) 0.81
Men 1.25 (0.57-2.75) 0.57
Angina 3.50 (1.62-7.58) 0.001 2.53 (1.11-5.74) 0.03
NYHA II 4.86 (2.25-10.48) lt0.0001
Syncope 3.54 (1.51-8.30) 0.004
Paroxysmal or chronic AF 2.24 (1.00-5.01) 0.05
NSVT 2.11 (0.92-4.84) 0.08
LBBB on ECG 1.16 (0.49-2.75) 0.73
Left atrial dimension 1.18 (1.04-1.33) 0.008
LV end-diastolic dimension 1.00 (0.93-1.07) 0.95
EF 0.94 (0.87-1.02) 0.14
Maximal LV thickness 1.19 (1.08-1.30) lt0.0001
Rest LV obstruction (gt30 mmHg) 6.52 (2.93-14.51) lt0.0001 2.70 (1.14-6.39) 0.02
Moderate to severe mitral regurg. 2.96 (1.23-7.12) 0.01
CFR lt2 7.61 (2.61-22.16) lt0.0001 4.30 (1.34-13.78) 0.01
ECG changes 2.38 (0.93-6.08) 0.07
Cortigiani, for the EPIC-FR. Submitted
41
Event-rates according to CFR
n 68 p lt 0.0001
CFR gt2 (79)
CFR lt2 (17)
CFR lt2 CFR gt2
Cortigiani, for the EPIC-FR. Submitted
42
Functional aspects of coronary circulation
Ischemia
CFR
43
Conclusions

• CFR evaluation of LAD by transthoracic Doppler
• is highly feasible (gt90)
• 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
• if effective to risk stratify patients with
  dilated and hypertrophic cardiomyopathy.

44
Coronary anatomic and prognostic CFR conditions
Mild-to-Moderate CAD
Moderate- to-severe CAD
Microvascular disease
Normal
Coronary angiography
Wall motion
STRESS
CFR

-



Prognostic impact
Cortigiani, for the EPIC-FR. JACC 2007501354
45
Diagnostic value of CFR for LAD disease
N pts Feasibility Sensitivity Specificity Accuracy
Hozumi JACC 1998 18 78 94 100 98
Caiati JACC 1999 138 88 88 76 87
Pizzuto Am J Cardiol 2003 45 96 97 91 93
Ruscazio JACC 2003 53 97 78 93 80
Nohotomi JASE 2003 110 92 94 65 81
Rigo Am J Cardiol 2003 230 94 81 84 83
EPIC-FR 2007 1,243 92 91 73 77
46
Diagnostic value of CFR for RCA disease
N pts Feasibility Sensitivity Specificity Accuracy
Voci Am J Cardiol 2002 81 54 89 96 -
Takeuchi JASE 2004 151 83 91 75 83
Rigo Cardiovasc Ultras 2005 446 68 89 72 81
47
CFR and stresses
X
X
X
CFR
X
X
EXE
ADO
DIPY
REST
DOBU
Iskandrian. J Nucl Cardiol 1994194
48
CFR with vasodilator agents
Adenosine Dipyridamole
Patient tolerance Lower Higher
Drug cost 100 Euros 1 Euro
Hyperventilation Higher Lower
Vasodilator effect onset Seconds (30) Minutes (2-3)
Combined wall motion and CFR Difficult Possible
Multiple coronary imaging Difficult Possible
Picano. Stress Echocardiography. 4th ed, 2003
49
Patients
CFR gt 2 (n37) CFR lt 2 (n31) p value
Age 5912 5711 0.59
Men 65 52 0.27
Angina 14 45 0.004
NYHA class 1.30.4 1.40.5 0.22
Syncope 3 29 0.02
Paroxysmal or chronic AF 14 35 0.03
NSVT 13 23 0.19
LBBB on ECG 24 26 0.89
Left atrial dimension (mm) 424 454 0.02
LV end-diastolic dimension (mm) 505 505 0.92
LV end-sistolic dimension (mm) 305 316 0.57
EF 585 596 0.30
Maximal LV thickness (mm) 173 204 lt0.0001
Rest LV obstruction (gt30 mmHg) 5 55 lt0.0001
Moderate to severe mitral regurg. 8 23 0.09
CFR on LAD 2.20.4 1.80.1 lt0.0001
ECG changes 30 42 0.29
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