Impaired Peripheral Endothelial Function Assessed by Digital Reactive Hyperemia Peripheral Arterial Tonometry and Risk of In-Stent Restenosis

Naohiro Komura, Kenichi Tsujita, Kenshi Yamanaga, Kenji Sakamoto, Koichi Kaikita, Seiji Hokimoto, Satomi Iwashita, Takashi Miyazaki, Tomonori Akasaka, Yuichiro Arima, Eiichiro Yamamoto, Yasuhiro Izumiya, Megumi Yamamuro, Sunao Kojima, Shinji Tayama, Seigo Sugiyama, Kunihiko Matsui, Sunao Nakamura, Kiyoshi Hibi, Kazuo Kimura, Satoshi Umemura, Hisao Ogawa, Naohiro Komura, Kenichi Tsujita, Kenshi Yamanaga, Kenji Sakamoto, Koichi Kaikita, Seiji Hokimoto, Satomi Iwashita, Takashi Miyazaki, Tomonori Akasaka, Yuichiro Arima, Eiichiro Yamamoto, Yasuhiro Izumiya, Megumi Yamamuro, Sunao Kojima, Shinji Tayama, Seigo Sugiyama, Kunihiko Matsui, Sunao Nakamura, Kiyoshi Hibi, Kazuo Kimura, Satoshi Umemura, Hisao Ogawa

Abstract

Background: Drug-eluting stents are replacing bare-metal stents, but in-stent restenosis (ISR) remains a problem. Reactive hyperemia index (RHI) assessed by peripheral arterial tonometry evaluates endothelial function noninvasively. We prospectively assessed the prognostic value of RHI in predicting ISR after percutaneous coronary intervention.

Methods and results: RHI was measured before percutaneous coronary intervention and at follow-up (F/U) angiography (F/U RHI; 6 and 9 months post bare-metal stents- and drug-eluting stents- percutaneous coronary intervention, respectively) in 249 consecutive patients. At F/U, ISR (stenosis >50% of diameter) was seen in 68 patients (27.3%). F/U natural logarithm (RHI) was significantly lower in patients with ISR than in those without (0.52±0.23 versus 0.65±0.27, P<0.01); no between-group difference in initial natural logarithm (RHI) (0.60±0.26 versus 0.62±0.25, P=0.56) was seen. By multivariate logistic regression analysis, even after adjusting for other significant parameters in univariate analysis, F/U natural logarithm (RHI) independently predicted ISR (odds ratio: 0.13; 95% CI: 0.04-0.48; P=0.002). In receiver operating-characteristic analysis, F/U RHI was the strongest predictor of ISR (area under the curve: 0.67; 95% CI: 0.60-0.75; P<0.01; RHI <1.73 had 67.6% sensitivity, 64.1% specificity); area under the curve significantly improved from 0.62 to 0.70 when RHI was added to traditional ISR risk factors (P=0.02). Net reclassification index was significant after addition of RHI (26.5%, P=0.002).

Conclusions: Impaired RHI at F/U angiography independently correlated with ISR, adding incremental prognostic value to the ISR-risk stratification following percutaneous coronary intervention.

Clinical trial registration: URL: https://www.clinicaltrials.gov/. Unique identifier: NCT02131935.

Keywords: endothelial dysfunction; reactive hyperemia; reactive hyperemia–peripheral arterial tonometry; restenosis; risk factor; stent.

© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Figures

Figure 1
Figure 1
Flowchart of patient enrollment in the present study. During the study F/U period, F/U CAG was not performed in 100 patients, and F/U RH‐PAT was not performed in 19 patients. Excluding these subjects, 249 patients represent the study population in the current study. BMS indicates bare‐metal stent; CAG, coronary angiography; DES, drug‐eluting stent; F/U, follow‐up; ISR, in‐stent restenosis; PCI, percutaneous coronary intervention; RH‐PAT, reactive hyperemia–peripheral arterial tonometry.
Figure 2
Figure 2
Representative records of RH‐PAT signals and CAG in ISR and non‐ISR patients. A, Typical ISR patient. B, Non‐ISR patient. CAG indicates coronary angiography; F/U, follow‐up; ISR, in‐stent restenosis; ln‐RHI, natural logarithm of reactive hyperemia–peripheral arterial tonometry index; PCI, percutaneous coronary intervention; RH‐PAT, reactive hyperemia–peripheral arterial tonometry.
Figure 3
Figure 3
RHI and ISR. ln(RHI) in ISR and non‐ISR patients at (A) index percutaneous coronary intervention and (B) F/U. Bars represent averages of the ln(RHI) in each group; error bars indicate 1 SD. F/U indicates follow‐up; ISR, in‐stent restenosis; ln(RHI), natural logarithm of reactive hyperemia–peripheral arterial tonometry index.
Figure 4
Figure 4
ROC curves to identify ISR. ROC curves for RHI identifying patients with ISR for (A) all patients, (B) patients with DES implantation, and (C) patients with BMS implantation. AUC for detection of ISR was 0.67 (95% CI: 0.60–0.75; P<0.01) of RHI in all patients, 0.67 (95% CI: 0.57–0.77; P<0.01) of RHI in DES‐only patients alone, and 0.68 (95% CI: 0.55–0.81; P=0.01) of RHI in BMS‐only patients. AUC indicates area under the curve; BMS, bare‐metal stent; DES, drug‐eluting stent; ISR, in‐stent restenosis; RHI, reactive hyperemia–peripheral arterial tonometry index; ROC, receiver operating characteristic.
Figure 5
Figure 5
Comparison of ROC curves to identify ISR between traditional risk factors only and traditional risk factors+RHI in all patients, DES patients, and BMS patients. ROC curves for traditional risk factors only and traditional risk factors+RHI to identify ISR in (A) all patients, (B) patients with DES implantation, and (C) patients with BMS implantation. AUC indicates area under the curve; BMS, bare‐metal stent; DES, drug‐eluting stent; ISR, in‐stent restenosis; RHI, reactive hyperemia–peripheral arterial tonometry index; ROC, receiver operating characteristic.

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