Peripheral endothelial function and cardiovascular events in high-risk patients

Yasushi Matsuzawa, Seigo Sugiyama, Hitoshi Sumida, Koichi Sugamura, Toshimitsu Nozaki, Keisuke Ohba, Junichi Matsubara, Hirofumi Kurokawa, Koichiro Fujisue, Masaaki Konishi, Eiichi Akiyama, Hiroyuki Suzuki, Yasuhiro Nagayoshi, Megumi Yamamuro, Kenji Sakamoto, Satomi Iwashita, Hideaki Jinnouchi, Masataka Taguri, Satoshi Morita, Kunihiko Matsui, Kazuo Kimura, Satoshi Umemura, Hisao Ogawa, Yasushi Matsuzawa, Seigo Sugiyama, Hitoshi Sumida, Koichi Sugamura, Toshimitsu Nozaki, Keisuke Ohba, Junichi Matsubara, Hirofumi Kurokawa, Koichiro Fujisue, Masaaki Konishi, Eiichi Akiyama, Hiroyuki Suzuki, Yasuhiro Nagayoshi, Megumi Yamamuro, Kenji Sakamoto, Satomi Iwashita, Hideaki Jinnouchi, Masataka Taguri, Satoshi Morita, Kunihiko Matsui, Kazuo Kimura, Satoshi Umemura, Hisao Ogawa

Abstract

Background: Endothelial dysfunction is a key component of vascular vulnerability. Reactive hyperemia index (RHI), as assessed by the peripheral arterial tonometry, can noninvasively evaluate endothelial function. This study was designed to determine the additional prognostic value of endothelial function to the Synergy Between PCI With Taxus and Cardiac Surgery Score (SYNTAXsc) and the Framingham Risk Score (FRS) in predicting cardiovascular events in high-risk patients.

Methods and results: We undertook a two-center prospective study in 528 stable patients at high-risk for cardiovascular events from the years 2006-2011. The RHI was measured before coronary angiography and coronary complexity was assessed by SYNTAXsc. After optimal therapies including coronary revascularization, there was follow-up with patients until August 2012. Cardiovascular events consist of cardiovascular death, myocardial infarction, unstable angina, ischemic stroke, coronary revascularization, heart failure-induced hospitalization, aortic disease, and peripheral arterial disease. During 1468 person-years of follow-up, 105 patients developed cardiovascular events. Multivariate Cox proportional hazards analysis identified B-type natriuretic peptide (BNP), SYNTAXsc, and RHI as independent cardiovascular event predictors (hazard ratio [95% confidence interval]: natural logarithm of BNP per 0.1: 1.019 [1.002 to 1.037]; P=0.023, SYNTAXsc per tertile: 2.426 [1.825 to 3.225]; P<0.0001, RHI per 0.1: 0.761 [0.673 to 0.859]; P<0.0001). When RHI was added to the FRS, BNP, and SYNTAXsc, net reclassification index was significantly improved (27.5%; P<0.0001), with a significant increase in the C-statistic (from 0.728 [0.679 to 0.778] to 0.766 [0.726 to 0.806]; P=0.031).

Conclusions: Advanced endothelial dysfunction significantly correlated with near future cardiovascular events in high-risk patients. This physiological vascular measurement improved risk discrimination when added to the FRS, BNP, and SYNTAXsc.

Clinical trial registration url: clinicaltrials.gov (http://www.clinicaltrials.gov). Unique identifier: NCT00737945.

Keywords: cardiovascular events; endothelial dysfunction; follow‐up study.

Figures

Figure 1.
Figure 1.
Representative RH‐PAT signals. A, RH‐PAT ratio was calculated with the following equation: RH‐PAT ratio=(C/D)/(A/B). The representative results of RH‐PAT of the patient without cardiovascular event (B) and the patient with cardiovascular event (C). RHI indicates reactive hyperemia‐peripheral arterial tonometry index; RH‐PAT, reactive hyperemia‐peripheral arterial tonometry.
Figure 2.
Figure 2.
Study protocol flow chart. CAD indicates coronary artery disease; RHI, reactive hyperemia‐peripheral arterial tonometry index.
Figure 3.
Figure 3.
RHI and cardiovascular events. A, These bars represent RHI averages for each group. T‐bars indicate standard deviation. B, Kaplan‐Meier analysis for cardiovascular event probability in high‐risk patients based on a median RHI value of 0.531. CV indicates cardiovascular; RHI, reactive hyperemia‐peripheral arterial tonometry index.
Figure 4.
Figure 4.
Kaplan‐Meier analysis for cardiovascular event probability in high‐risk patients based on BNP, SYNTAXsc, and RHI. (n=528). A, Analysis in subgroups stratified by RHI and BNP. B, Analysis in subgroups stratified by RHI and SYNTAXsc. Based on each cut‐off point (median value) of RHI, BNP and SYNTAX Score. RHI 0.531, BNP 28.6 pg/mL, and SYNTAX Score 13.0. BNP indicates B‐type natriuretic peptide; RHI, reactive hyperemia‐peripheral arterial tonometry index; SYNTAXsc, Synergy Between PCI With Taxus and Cardiac Surgery Score.
Figure 5.
Figure 5.
RHI and cardiovascular events in 442 CAD patients. A, These bars represent averages of the RHI in each group (CV events [−] [n=340], CV events [+] [n=102]). T‐bars indicate standard deviation. B, Kaplan‐Meier analysis for the probability of cardiovascular events in CAD patients based on median value of RHI (0.501). CAD indicates coronary artery disease; CV, cardiovascular; RHI, reactive hyperemia‐peripheral arterial tonometry index.
Figure 6.
Figure 6.
Kaplan‐Meier analysis for cardiovascular event probability in CAD patients based on BNP, SYNTAXsc, and RHI. (n=442). A, Analysis in subgroups stratified by RHI and BNP. B, Analysis in subgroups stratified by RHI and SYNTAX score. Based on each cut‐off point (median value) of RHI, BNP, and SYNTAX Score. RHI 0.501, BNP 31.7 pg/mL, and SYNTAX Score 15.8. BNP indicates B‐type natriuretic peptide; CAD, coronary artery disease; RHI, reactive hyperemia‐peripheral arterial tonometry index; SYNTAXsc, Synergy Between PCI With Taxus and Cardiac Surgery Score.

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