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Digital Assessment of Endothelial Function and Ischemic Heart Disease in Women

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,

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Digital Assessment of Endothelial Function and Ischemic Heart Disease in Women

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  1. Digital Assessment of Endothelial Function andIschemic 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

  2. Background (1) • Coronary artery disease is the leading cause of mortality for post-menopausal women. (Mieres JH. Circulation. 2005;111(5):682-696.) • 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.) • 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

  3. Background (2) • 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. • 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

  4. Endo-PAT2000(Itamar Medical, Caesarea, Israel) Fingertip tonometry Computer for analysis Tourniquet

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

  6. Endo-PAT Advantages • 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.) • RH-PAT is related to multiple traditional and metabolic cardiovascular risk factors. (Naomi M. Hamburg et al. Circulation, 2008; 117: 2467-2474.) • 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

  7. 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

  8. 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

  9. Methods • RH-PAT was measured before cardiac catheterization in158 stable women scheduled for hospitalization to examine chest pain. • RH-PAT studies were performed in the fasting state early morning after > 3days discontinuation of vasodilators. • 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

  10. n = 158 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) Stable Women with angina-like chest pain n = 140 RH-PAT measurement Coronary angiography ≥50% Organic stenosis 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 Negative n = 34 Epicardial coronary spasm with myocardial lactate production CBF decrease without epicardial coronary spasm with myocardial lactate production Adenosine-Coronary flow reserve and stress thallium-SPECT Abnormal Normal Obstructive-CAD n = 68 Non-IHD n = 30 Epicardial coronary spasm n = 32 Microvascular spasm n = 6 Microcirculatory insufficiency n = 4 NOCAD (n = 42) IHD (n = 110) Matuzawa Y, Sugiyama S, Kimura K, Ogawa H, et al JACC 2010 in press

  11. Data are mean (SD), median values [25 to 75th 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

  12. Data are mean (SD), median values [25 to 75th 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

  13. Results – 2 Endothelial function attenuated in patients with IHD (A) (B) P < 0.001 P < 0.001 P < 0.001 P = 0.82 2.8 2.8 2.6 2.6 2.4 2.4 2.2 2.2 RH-PAT index 2.0 RH-PAT index 2 1.8 1.8 1.6 1.6 1.4 1.4 1.2 1.2 Non-IHD (n = 30) Obstructive CAD (n = 68) NOCAD (n = 42) Non-IHD (n = 30) IHD (n = 110) Matuzawa Y, Sugiyama S, Ogawa H, et al JACC 2010 in press

  14. Results – 3 Coronary Endothelial Functions Decreased in Patients with NOCAD Fingertip RH-PAT well Correlated with Coronary Endothelial Function. P < 0.001 (A) (B) 1.2 2.8 1 2.3 ACh20-induced CBF ratio .8 Ln(RH-PAT index) 1.8 .6 r = 0.51 P < 0.001 1.3 .4 .8 .2 ACh20-induced CBF ratio .5 1 1.5 2 2.5 3 3.5 4 Non-IHD (n = 20) NOCAD (n = 31) CBF: coronary blood flow Matuzawa Y, Sugiyama S, Ogawa H, et al JACC 2010 in press

  15. Results – 5 ROC analysis to identify patients with Obstructive-CAD Reynolds Risk Score (RRS) was Superior to RH-PAT. • Obstructive-CAD All patients 1.0 Sensitivity 0.5 RH-PAT (AUC = 0.66, P < 0.001) RRS (AUC = 0.78, P < 0.001) 0 0 0.5 1.0 1-Specificity

  16. Results – 5 ROC Analysis to Identify Patients with Overall IHD. RH-PAT was Superior to Reynolds Risk Score (RRS). (B) IHD All patients 1.0 Sensitivity RH-PAT (AUC = 0.86, P < 0.001) 0.5 RRS (AUC = 0.73, P < 0.001) 0 0 0.5 1.0 1-Specificity Matuzawa Y, Sugiyama S, Ogawa H, et al JACC 2010 in press

  17. 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 1.0 RH-PAT (AUC = 0.85, P < 0.001) RRS (AUC = 0.59, P = 0.22) Sensitivity Cutoff value of RH-PAT of <1.82 Sensitivity 81% Specificity 80% 0.5 RRS: Reynolds Risk Score 0 0 0.5 1.0 Matuzawa Y, Sugiyama S, Ogawa H, et al JACC 2010 in press 1-Specificity

  18. Summary • 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. • Fingertip RH-PAT index correlated significantly with coronary endothelial function assessed by ACh induced-CBF increase. • 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

  19. Conclusions • Fingertip RH-PAT could non-invasively predict the presence of IHD especially NOCAD prior to CAG. • 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

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