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Digital Assessment of Endothelial Function and Ischemic Heart Disease in Women Yasushi Matsuzawa, Seigo Digital Assessment of Endothelial Function and Ischemic Heart Disease in Women Yasushi Matsuzawa, Seigo Sugiyama, Hitoshi Sumida, Koichi Sugamura, Toshimitsu Nozaki, Keisuke Ohba, Masaaki Konishi, Junichi Matsubara, Koichi Kaikita, Sunao Kojima, Yasuhiro Nagayoshi, Megumi Yamamuro, Yasuhiro Izumiya, Satomi Iwashita, Kunihiko Matsui, Kazuo Kimura, Satoshi Umemura, Hisao Ogawa Department of Cardiovascular Medicine, Kumamoto University Clinical Education Center, Kumamoto University Division of Cardiology, Yokohama City University Medical Center Department of Medical Science and Cardiorenal Medicine, Yokohama City University

Background (1) l Coronary artery disease is the leading cause of mortality for postmenopausal Background (1) l Coronary artery disease is the leading cause of mortality for postmenopausal women.   (Mieres JH. Circulation. 2005; 111(5): 682 -696. ) l The Women’s Ischemia Syndrome Evaluation study documented that 69% of women suspected of ischemic heart disease have no significant coronary artery stenoses (i. e. , >50% stenosis) in any major coronary artery. (Merz CN et al. J Am Coll Cardiol. 1999; 33(6): 1453 -1461. ) l As for the patients with the myocardial ischemia, it was also demonstrated without obstructive coronary artery disease (CAD) to be a high-risk state.   (Bugiardini R et al. Jama. 2005; 293(4): 477 -484. ) (Johnson BD et al. Circulation. 2004; 109(24): 2993 -2999. ) Matuzawa Y, Sugiyama S, Kimura K, Ogawa H, et al JACC 2010 in press

Background (2) l The pathogenesis of non-obstructive coronary artery disease (NOCAD) is not clear Background (2) l The pathogenesis of non-obstructive coronary artery disease (NOCAD) is not clear at present but could be due to physiological abnormality in coronary circulation; coronary spastic angina (CSA), coronary microvascular spasm, or microcirculatory insufficiency. l The vascular endothelial function was attenuated in patients with obstructive-CAD. Furthermore, NOCAD have shown to be associated with coronary endothelial dysfunction. (Rosso R et al. NEJM. 1999; 340(2): 115 -126. ) (Mohri M et al. Lancet. 1998; 351(9110): 1165 -1169. ) (Campisi R et al. Int J Clin Pract. 2008; 62(2): 300 -307. ) (Yasue H et al. Intern Med. 1997; 36(11): 760 -765. ) Matuzawa Y, Sugiyama S, Kimura K, Ogawa H, et al JACC 2010 in press

Endo-PAT 2000 (Itamar Medical, Caesarea, Israel) Fingertip tonometry Computer for analysis Tourniquet Endo-PAT 2000 (Itamar Medical, Caesarea, Israel) Fingertip tonometry Computer for analysis Tourniquet

Reactive Hyperemia Peripheral Arterial Tonometry (RH-PAT) 5 min Control arm Study arm 5 min Reactive Hyperemia Peripheral Arterial Tonometry (RH-PAT) 5 min Control arm Study arm 5 min B Cuff inflation D 10 min A Occlusion Cuff deflation C C A RH-PAT index = / B ×Baseline correction D Test / baseline ratio of tested arm Test / baseline ratio of control arm

Endo-PAT Advantages 1. 2. 3. 4. 5. Non-invasive Easy to use, non user-dependent Automatic Endo-PAT Advantages 1. 2. 3. 4. 5. Non-invasive Easy to use, non user-dependent Automatic analysis Reproducible The response depends on NO from vascular endothelium mainly. (Anju Nohria et al. J Appl Physiol, Aug 2006; 101: 545 – 548. ) 6. RH-PAT is related to multiple traditional and metabolic cardiovascular risk factors. (Naomi M. Hamburg et al. Circulation, 2008; 117: 2467 -2474. ) 7. Predict cardiovascular events (Rubinstein R et al. J Eur Heart J 2010; Feb E-pub. ) Matuzawa Y, Sugiyama S, Kimura K, Ogawa H, et al JACC 2010 in press

Improvement of Endothelial Dysfunction is Important to Reduce Risk of Cardiovascular Disease The treatment Improvement of Endothelial Dysfunction is Important to Reduce Risk of Cardiovascular Disease The treatment of established risk factors can not improve endothelial dysfunction enough in some patients. Kitta Y. et al. JACC 2008. Matuzawa Y, Sugiyama S, Kimura K, Ogawa H, et al JACC 2010 in press

Objective • The purpose of this study was to assess the utility of digital Objective • The purpose of this study was to assess the utility of digital RH-PAT in predicting ischemic heart disease (IHD), including obstructive-CAD and NOCAD, in women. Matuzawa Y, Sugiyama S, Kimura K, Ogawa H, et al JACC 2010 in press

Methods l RH-PAT was measured before cardiac catheterization in 158 stable women scheduled for Methods l RH-PAT was measured before cardiac catheterization in 158 stable women scheduled for hospitalization to examine chest pain. l RH-PAT studies were performed in the fasting state early morning after > 3 days discontinuation of vasodilators. l NOCAD was diagnosed by angiography with measurements of coronary blood flow (CBF) and cardiac lactate production during intra-coronary acetylcholine (ACh) provocation test and the cardiac scintigraphy with stress tests. Matuzawa Y, Sugiyama S, Kimura K, Ogawa H, et al JACC 2010 in press

n = 158 Stable Women with angina-like chest pain n = 140 RH-PAT measurement n = 158 Stable Women with angina-like chest pain n = 140 RH-PAT measurement Coronary angiography ≥ 50% Organic stenosis Excluded (total n = 18) Severe aortic valve regurgitation (n = 1) Severe aortic valve stenosis (n = 1) Hypertrophic cardiomyopathy (n = 6) Uncontrolled hypertension (n = 1) Severe collagen disease (n = 6) Neuromuscular disease (n = 2)  Incomplete cardiac catheter data (n = 1) Non-obstructive coronary artery n = 68 n = 72 ACh-provocation test Measurement of myocardial lactate production and coronary blood flow Ischemic ST change and chest pain Epicardial coronary spasm with myocardial lactate production Obstructive-CAD n = 68 CBF decrease without epicardial coronary spasm with myocardial lactate production Epicardial coronary spasm n = 32 Microvascular spasm n=6 Negative n = 34 Adenosine-Coronary flow reserve and stress thallium-SPECT Abnormal Microcirculatory insufficiency n=4 Normal Non-IHD n = 30 NOCAD (n = 42) IHD (n = 110) Matuzawa Y, Sugiyama S, Kimura K, Ogawa H, et al JACC 2010 in press

Table 1. Baseline clinical characteristics of 140 women. N Age (years) Body mass index Table 1. Baseline clinical characteristics of 140 women. N Age (years) Body mass index (kg/m 2) Hypertension (%) Diabetes (%) Dyslipidemia (%) Currently smoking (%) Family history of CAD (%) Systolic BP (mm. Hg) Diastolic BP (mm. Hg) FBG (mg/dl) Hemoglobin A 1 c (%) HOMA-IR Non-IHD 30 63 (10) 23 (3) 53 20 67 3 3 124 (17) 77 (13) 89 [85 to 94] 5. 5 (0. 6) 1. 0 [0. 8 to 1. 7] Obstructive-CAD 68 73 (9) * 24 (5) 84 * 50 * 91 * 7 19 131 (20) 72 (12) 97 [88 to 115] 6. 1 (1. 2) * 1. 4 [1. 0 to 2. 5] * NOCAD 42 64 (10) + 24 (4) 62 + 29 + 64 + 14 21 * 130 (17) 78 (12) + 92 [86 to 105] 5. 6 (1. 0) + 1. 4 [0. 8 to 1. 8] Data are mean (SD), median values [25 to 75 th percentile range] or %. *Significantly different from Non-IHD. + Significantly different from Obstructive-CAD. Matuzawa Y, Sugiyama S, Ogawa H, et al JACC 2010 in press

Table 1. Baseline clinical characteristics. (Continued) N Total / HDL cholesterol ratio Triglycerides (mg/dl) Table 1. Baseline clinical characteristics. (Continued) N Total / HDL cholesterol ratio Triglycerides (mg/dl) LVEF (%) BNP (pg/ml) Hs-CRP (mg/l) Reynolds Risk Score (%) 25~50% coronary stenosis (%) Aspirin (%) Statins (%) Calcium channel blockers (%) ACE-I or ARB (%) b-blockers (%) Non-IHD 30 3. 5 (1. 2) 92 [65 to 123] 66 (7) 18 [10 to 26] 0. 5 [0. 3 to 1. 0] 1. 3 [0. 5 to 3. 5] 33 27 33 46 27 3 Obstructive-CAD NOCAD 68 42 3. 5 (1. 1) 3. 3 (0. 9) 101 [76 to 136] 99 [80 to 139] 65 (7) 66 (5) 48 [21 to 120] * 20 [12 to 30] + 1. 2 [0. 5 to 2. 8] * 0. 5 [0. 3 to 0. 9] + 5. 6 [2. 6 to 10. 2] * 1. 8 [1. 0 to 4. 0] + 43 90 * 46 + 79 * 38 + 71 * 49 + 62 * 29 + 46 * 0+ Data are mean (SD), median values [25 to 75 th percentile range] or %. *Significantly different from Non-IHD. + Significantly different from Obstructive-CAD. Matuzawa Y, Sugiyama S, Ogawa H, et al JACC 2010 in press

Results – 2 Endothelial function attenuated in patients with IHD (A) (B) P < Results – 2 Endothelial function attenuated in patients with IHD (A) (B) P < 0. 001 P = 0. 82 2. 8 2. 6 2. 4 2. 2 2 1. 8 1. 6 1. 4 1. 2 2. 6 RH-PAT index P < 0. 001 2. 4 2. 2 2. 0 1. 8 1. 6 1. 4 1. 2 Non-IHD (n = 30) IHD (n = 110) Non-IHD Obstructive NOCAD (n = 30) (n = 42) (n = 68) Matuzawa Y, Sugiyama S, Ogawa H, et al JACC 2010 in press

Results – 3 (A) Fingertip RH-PAT well Correlated with Coronary Endothelial Function. P < Results – 3 (A) Fingertip RH-PAT well Correlated with Coronary Endothelial Function. P < 0. 001 (B) 1. 2 2. 8 Ln(RH-PAT index) ACh 20 -induced CBF ratio Coronary Endothelial Functions Decreased in Patients with NOCAD 2. 3 1. 8 1. 3. 8 Non-IHD (n = 20) NOCAD (n = 31) 1. 8. 6. 4. 2 r = 0. 51 P < 0. 001. 5 ACh 20 -induced CBF 3 ratio 1 1. 5 2 2. 5 3. 5 4 CBF: coronary blood flow Matuzawa Y, Sugiyama S, Ogawa H, et al JACC 2010 in press

Table 2. Logistic regression analysis for the presence of IHD in female patients complaining Table 2. Logistic regression analysis for the presence of IHD in female patients complaining of chest pain.   Variable Simple Regression Multiple Regression OR 95%CI P value Age (per year) 1. 06 1. 02 - 1. 10 0. 004 0. 99 0. 92 - 1. 07 0. 81 BMI (per kg/m 2) 1. 06 0. 95 - 1. 18 0. 28 Currently smoking (yes) 3. 22 0. 40 - 26. 0 0. 27 Systolic BP (per mm. Hg) 1. 02 1. 00 - 1. 05 0. 06 Diastolic BP (per mm. Hg) 0. 98 0. 95 - 1. 01 0. 24 Ln [FBG] (per 0. 1) 1. 23 0. 96 - 1. 57 0. 10 Total / HDL cholesterol (per 1) 0. 95 0. 65 - 1. 42 0. 81 Ln [Triglycerides] (per 0. 1) 1. 03 0. 94 - 1. 12 0. 54 Ln [BNP] (per 0. 1) 1. 05 1. 01 - 1. 09 0. 01 1. 03 0. 98 - 1. 09 0. 21 Ln [Hs. CRP] (per 0. 1) 1. 01 0. 99 - 1. 03 0. 31 LVEF (per %) 0. 98 0. 92 - 1. 05 0. 60 Ln [Reynolds Risk Score] (per 0. 1) 1. 07 1. 04 - 1. 11 <0. 001 1. 06 1. 00 - 1. 13 0. 05 Ln [RH-PAT index] (per 0. 1) 0. 50 0. 38 - 0. 65 <0. 001 0. 51 0. 38 - 0. 68 <0. 001

Results – 5 ROC analysis to identify patients with Obstructive-CAD Reynolds Risk Score (RRS) Results – 5 ROC analysis to identify patients with Obstructive-CAD Reynolds Risk Score (RRS) was Superior to RH-PAT. (A) Obstructive-CAD All patients Sensitivity 1. 0 0. 5 RH-PAT (AUC = 0. 66, P < 0. 001) RRS (AUC = 0. 78, P < 0. 001) 0 0 0. 5 1 -Specificity 1. 0

Results – 5 ROC Analysis to Identify Patients with Overall IHD. RH-PAT was Superior Results – 5 ROC Analysis to Identify Patients with Overall IHD. RH-PAT was Superior to Reynolds Risk Score (RRS). (B) IHD All patients Sensitivity 1. 0 RH-PAT (AUC = 0. 86, P < 0. 001) RRS (AUC = 0. 73, P < 0. 001) 0. 5 0 0 0. 5 1 -Specificity 1. 0 Matuzawa Y, Sugiyama S, Ogawa H, et al JACC 2010 in press

Results – 5 ROC Analysis to Identify Patients with NOCAD in Women wtihout Obstructive-CAD. Results – 5 ROC Analysis to Identify Patients with NOCAD in Women wtihout Obstructive-CAD. Only RH-PAT could Predict. (C) NOCAD Patients without obstructive-CAD RH-PAT (AUC = 0. 85, P < 0. 001) RRS (AUC = 0. 59, P = 0. 22) Sensitivity 1. 0 Cutoff value of RH-PAT of <1. 82 Sensitivity 81% Specificity 80% 0. 5 RRS: Reynolds Risk Score 0 0 0. 5 1 -Specificity 1. 0 Matuzawa Y, Sugiyama S, Ogawa H, et al JACC 2010 in press

Summary l Endothelial functions evaluated by RH-PAT were significantly impaired in patients with NOCAD, Summary l Endothelial functions evaluated by RH-PAT were significantly impaired in patients with NOCAD, and such impairments were equivalent to that seen in patients with obstructive-CAD. l Fingertip RH-PAT index correlated significantly with coronary endothelial function assessed by ACh induced. CBF increase. l Reynolds Risk Score and RH-PAT index significantly predicted IHD. RH-PAT was particularly superior in predicting NOCAD. Matuzawa Y, Sugiyama S, Ogawa H, et al JACC 2010 in press

Conclusions l Fingertip RH-PAT could non-invasively predict the presence of IHD especially NOCAD prior Conclusions l Fingertip RH-PAT could non-invasively predict the presence of IHD especially NOCAD prior to CAG. l RH-PAT is a potentially useful clinical test and can effectively identify high risk patients in women with chest pain. Matuzawa Y, Sugiyama S, Ogawa H, et al JACC 2010 in press