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Changes in Index of Microcirculatory Resistance during PCI in the Left Anterior Descending Coronary Artery in Relation to Total Length of Implanted Stents

Changes in Index of Microcirculatory Resistance during PCI in the Left Anterior Descending... Hindawi Journal of Interventional Cardiology Volume 2019, Article ID 1397895, 6 pages https://doi.org/10.1155/2019/1397895 Research Article Changes in Index of Microcirculatory Resistance during PCI in the Left Anterior Descending Coronary Artery in Relation to Total Length of Implanted Stents 1 1 1 Christina Ekenba¨ck, Fadi Jokhaji, Nikolaos Ostlund-Papadogeorgos, 1 1 2 1 1 Habib Mir-Akbari, Rikard Linder, Nils Witt , Mattias To¨rnerud, Bassem Samad, and Jonas Persson Division of Cardiovascular Medicine, Department of Clinical Sciences, Karolinska Institutet, Danderyd University Hospital, Stockholm, Sweden Department of Clinical Science and Education, Karolinska Institutet, Unit of Cardiology, So¨dersjukhuset, Stockholm, Sweden Correspondence should be addressed to Jonas Persson; jonas.persson@sll.se Received 14 August 2019; Revised 4 October 2019; Accepted 14 October 2019; Published 1 December 2019 Academic Editor: Viktor Kocˇka Copyright © 2019 Christina Ekenba¨ck et al. ­is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Aim. To investigate the relationship between stent length and changes in microvascular resistance during PCI in stable coronary artery disease (CAD). Methods and Results. We measured fractional Œow reserve (FFR), index of microcirculatory resistance (IMR), and coronary Œow reserve (CFR) before and after stenting in 42 consecutive subjects with stable coronary artery un- dergoing PCI with stent in the LAD. Patients that had very long stent length (38–78 mm) had lower FFR before stenting than patients that had long (23–37 mm) and moderate (12–22 mm) stent length (0.59 (±0.16), 0.70 (±0.12), and 0.75 (±0.07); p  0.002). FFR improved after stenting and more so in subjects with very long stent length compared to long and moderate stent length (0.27 (s.d ± 16), 0.15 (s.d ± 0.12), and 0.12 (s.d ± 0.07); p for interaction  0.013). Corrected IMR (IMR ) increased after stenting in corr subjects who had very long stent length, whereas IMR was lower after stenting in subjects who had long or moderate stent corr length (4.6 (s.d. ± 10.7), − 1.4 (s.d. ± 9,9), and − 4.2 (s.d. ± 7.8); p for interaction  0.009). Conclusions. Changes in IMR during PCI in the LAD in stable CAD seem to be related to total length of stents implanted, possibly inŒuencing post-PCI FFR. Larger studies are needed to conœrm the relationship. Index of microcirculatory resistance (IMR) is a vali- 1. Introduction dated measurement of coronary microvascular resistance Fractional Œow reserve (FFR) is a validated and reproducible [9], and high IMR (>25 units) can be considered to be a measure of the functional severity of a coronary artery lesion proxy for CMVD [10]. IMR is derived from thermodilu- [1, 2]. FFR-guided PCI with DES and optimal medical tion measurements at peak hyperaemia [9], thereby therapy (OMT) improves outcome and angina symptoms eliminating the variability of coronary resting Œow. Im- for patients with stable coronary artery disease compared to portantly, IMR is measured simultaneously with FFR [11]; OMT alone [3, 4]. Furthermore, higher post-PCI FFR is thus, the physiological signiœcance of epicardial lesions and the coronary microcirculatory function can be con- associated with better outcome [5, 6]. However, increased coronary microvascular resistance is associated with higher currently assessed. post-PCI FFR [7], and coronary microvascular dysfunction Whether epicardial stenosis a¤ects hyperaemic coro- (CMVD) is associated with long-term recurrence of reste- nary microvascular resistance is debated and data are nosis [8]. conŒicting. Studies have shown that PCI lowers 2 Journal of Interventional Cardiology microvascular resistance immediately after stenting [12– used for feasibility (70kg patient receives an infusion of 14], whereas other reports have shown that microvascular 700ml per hour, 80kg patient receives an infusion of 800ml resistance is independent of epicardial lesions [15–18]. +e per hour, and so on.). Furthermore, infusion rates of relationship between stent length and changes in micro- 160–180μg/kg/min are safe and recommended to receive vascular resistance is not known. We hypothesised that maximal hyperaemia [20, 21]. Again, three millilitres of cold there was no improvement, or even impairment, in mi- saline was injected in the LAD three times, and hyperaemic crovascular resistance post-PCI with very long total stent thermodilution curves (Tmn ) and distal (Pd) and prox- hyp length. For this purpose, we measured FFR, IMR, and imal (Pa) coronary pressure were recorded. Measurements coronary flow reserve (CFR) with thermodilution before were repeated after PCI in the LAD in the same position as and after stenting in 42 consecutive subjects with stable before stenting. coronary artery undergoing PCI with stent of the LAD. +e FFR was calculated by dividing Pd by Pa (Pd/Pa) during relationships between changes in coronary flow indices and hyperaemia. CFR was calculated as the ratio between Tmn base total stent length were analysed. and Tmn (Tmn /Tmn ). IMR was calculated as the hyp base hyp product of Tmn and Pd (Tmn ×Pd). IMR can be hyp hyp overestimated in subjects with FFR ≤0.80 due to collateral 2. Methods flow, and thus corrected IMR (IMR ) was calculated corr according to Yong [22]: IMR �Pa ×Tmn ×([1.35 ×Pd/ 2.1.Subjects. Consecutive patients, 18–85 years of age, with corr hyp Pa] − 0.32). an life expectancy of >2 years that were planned for coronary angiography due to stable coronary artery disease nd th were included between 2 of September 2015 and 20 of 2.3. Statistics. Median values and interquartile range (IQR) September 2017. Subjects were included before coronary are presented for continuous variables. Numbers and pro- anatomy was known. Patients with acute coronary syn- portions are presented for categorical variables. Stent length drome, congestive heart failure with ejection fraction was categorized into three different categories since the <39%, prior heart transplantation, prior coronary artery variable is ordinal and non-normally distributed; moderate by-pass grafting, hypertrophic cardiomyopathy, valvular (12–22mm), long (23–37mm), and very long (38–78mm) heart disease scheduled for surgery/intervention, cancer stent length. Linear regression was used to compare flow within three years of admission, peri- and/or myocarditis, indices between groups. Two-way repeated measures contrast allergy, atrial fibrillation with ventricular rate ANOVA analyses (Wilks-Lambda) were used to analyse >120, asthma bronchiale, and atrioventricular block II-III changes inIMR andCFR beforeandafterstenting inrelation were excluded. After coronary angiography, measure- to stent length group. Non-normally distributed variables, ments of FFR, CFR, and IMR in the LAD were conducted including IMR , were log-transformed before analysis. α corr irrespectively of coronary anatomy. Subjects with chronic was two-sided and set to 0.05. IBM SPSS Statistics 23.0 was total occlusion in the LAD, heavy calcification, or tortu- used for analyses. osity in the left main/LAD hindering safe passage of a guide-wire with pressure and temperature sensors were excluded at the discretion of the PCI operator. In total, 274 3. Results subjects were included after oral and written informed 3.1. Baseline Procedural Characteristics. Forty-two patients consent was obtained. In the current analysis, we report underwent stenting of the LAD and had flow indices pre- to post-PCI changes in FFR, CFR, and IMR in relation measured before and after stenting. Seven patients were to total stent length and other variables in subjects treated women, seven had diabetes mellitus, and two thirds of the with PCI in the LAD who had flow indices measured both patients had one-vessel disease (Table 1). A majority (90%) before and after PCI (n �42). Ethical permission was of the patients had Canadian Cardiovascular Society grade I approved by the Regional Ethical Review Board in and II angina pectoris. All patients were stented with Stockholm (no 2015/962–31). second generation drug-eluting stent (everolimus, n �23; zotarolimus, n �13; sirolimus, n �6). One patient in the 2.2. Flow Measurements. FFR, IMR, and CFR were mea- long stent length group (23–37mm) received a bio- sured in the LAD after initial coronary angiography and degradable vascular scaffold, and one patient in the very again after PCI of the LAD. A coronary guide-wire with long stent length group (38–78mm) was stented also in the pressure and temperature sensors (Pressure Wire X; Abbott left main. All patients were on double antiplatelet therapy. Inc., CA, USA) was advanced in the LAD (sensors>70mm Two patients were on ticagrelor, of which one was a non- from the catheter tip and distal to the lesion). +ree mil- responder to clopidogrel (Multiplate ADPtest) and the lilitres of cold saline was injected into the LAD, and ther- other patient was allergic to clopidogrel. A few (n �4) modilution curves were recorded. +e procedure was lesions were treated by direct stenting, a majority of the repeated in total three times calculating the mean transit stents were post-dilated (Table 2), and no debulking devices time (Tmn ). +en, adenosine (dosage of 167μg/kg/min) such as rotational atherectomy were used. Patients that had base was administered intravenously in a large cubital vein for very long stent length had lower FFR before stenting and two minutes to induce stable hyperaemia. A higher infusion higher Tmn after stenting than the other two groups hyp rate of adenosine 1mg/ml than in other studies [19, 20] was (Table 3). Journal of Interventional Cardiology 3 Table 1: Baseline characteristics. microcirculation after the procedure (on average 4.6 units IMR -change from pre-to post-PCI). Age, years (s.d.) 65.3 (8.2) corr Female gender, n (%) 7 (17) Total stent length can be considered to be a proxy for both Diabetes mellitus, n (%) 7 (17) atherosclerotic burden and complexity of PCI procedures. In Previous myocardial infarction, n (%) 5 (12) more complex PCI with very long total stent length, more Previous PCI, n (%) 9 (21) balloon dilatations, and interactions with a larger part of the Atrial flutter, n (%) 2 (5) vessel wall, the occurrence of impaired microcirculation and Smoking, n (%) rise in the resistance are likely more frequent than in less Never 24 (57) complex PCI, which explain our findings with elevated IMR Previous 13 (31) after PCI with very long stent length. Supporting this, is a Smoker 5 (12) randomized trial of direct stenting compared to stenting with Canadian Cardiovascular Society grade, n (%) predilatation (more complex technique), indicating that di- I 15 (36) rect stenting with fewer dilatations is less traumatic for the II 23 (55) coronary microcirculation as compared to conventional III 3 (7) stenting [23]. Elective PCI might impair resting microvas- IV 1 (2) cular perfusion [24] through several different mechanisms Body mass index (kg/m ), median (IQR) 27 (24–30) acutely elevating the coronary microcirculatory resistance; Total cholesterol (mmol/L), median (IQR) 4.3 (3.7–5.1) release of local vasoconstrictors [25], vasoconstriction [26], Low density lipoprotein cholesterol (mmol), 2.4 (1.9–3.1) impairment of endothelial function [27, 28], and distal em- median (IQR) HbA c (mmol/mol), median (IQR) 39 (35–42) bolization [29, 30]. Microvascular impairment is more likely Creatinine clearance (mL/min/1.73m ), median tooccurduringmorecomplexPCIand/orinverylonglesions 82 (69–96) (IQR) than in less complex interventions. Medication at inclusion Coronary microvascular disease is one of the limitations Aspirin 42 (100) when identifying ischemic lesions with FFR [21]. It is dif- Clopidogrel 40 (95) ficult to appreciate the effects of immediate (and possibly Ticagrelor 2 (5) transient) acute rise in coronary microcirculation resistance AII-receptor antagonists, n (%) 12 (29) corresponding to 4.6 units IMR on distal pressure in the corr Beta-blockers, n (%) 26 (62) LAD (P ) and subsequent elevation of FFR values after PCI. Nitrates, n (%) 10 (24) Studies have consistently shown that higher FFR values after Calcium antagonists, n (%) 13 (31) stenting is associated with lower MACE rates [5, 6, 31, 32]. A ACE inhibitors, n (%) 9 (21) recent meta-analysis of post-PCI FFR measurements in Lipid-lowering therapy at admission 32 (76) FAME-1 and FAME-2 showed that the best cut-off value for IQR �interquartile range. predicting two-year vessel-oriented composite endpoint (death, MI, revascularization) was 0.915, with a sensitivity of 3.2.ChangesinFlowIndices. Asexpected, FFR wasimproved 75% and specificity of 43%. However, the authors conclude after stenting and more so in subjects with very long stent that its predictive value is too low for optimization of PCI length (p for interaction �0.013; Figure 1(a)). Changes in procedures [32]. Assessing FFR in combination with post- IMR were related to stent length in LAD; IMR in- corr corr PCI IMR provides information about the treated epicardial creased after stenting in subjects who had very long stent lesion and the microcirculatory function immediately after length (38–78mm), whereas IMR was attenuated after corr the intervention. +is might improve sensitivity, specificity, stenting in subjects who had moderate or long (12–22mm and predictive value for future major adverse cardiovascular and 23–37mm, respectively) stent length (p for inter- events. +e interpretation of post-PCI FFR may benefit from action �0.009; Figure 1(b)). Changes in CFR were not re- concurrent assessment of the coronary microcirculation, but lated to stent length (Figure 1(c)). it needs to be evaluated in studies. Pre-PCI IMR is associated with post-PCI in a several 4. Discussion studies [12, 33, 34]. In our study, pre-PCI IMR are accounted 4.1. Implications. Our data shows that PCI with very long for in the analysis since we are studying changes in IMR stent length (≥38mm) in the LAD is associated with larger during PCI. Diabetes mellitus is associated with post-PCI IMR in a small study mixing acute coronary syndromes and improvement in FFR than in moderate or long stent length. +eimprovementinFFRwasaccompaniedbyariseinIMR stable coronary artery disease [33]. Diabetes mellitus was not corr an interaction term for changes in IMR in our study (data after stenting for very long stent length, whereas moderate and long stent length was associated with attenuated IMR . not shown), possibly due to low power with only seven corr +e findings have two important implications: (i) PCI subjects with diabetes mellitus. with very long total stent length in patients with stable In experimental human and animal studies, assessment coronary artery disease in the elective setting is associated of IMR is independent of artificial stenosis created by bal- with a rise in resistance after PCI in the coronary micro- loons and a vascular occluder [17, 18], and studies of IMR circulation and (ii) improved FFR values after PCI with very before and after PCI have shown that there are no alterations long total stent length may be partly explained by the im- in microvascular resistance when collateral flow is taken into mediate rise in the resistance of the coronary account [15, 16]. However, other studies have shown that 4 Journal of Interventional Cardiology Table 2: Procedural characteristics. Total stent length in LAD 12–22mm 23–37mm 38–78mm n �14 n �14 n �14 1 14 9 5 Number of stents in LAD 2 0 5 7 3 0 0 2 Yes 1 3 0 Direct stenting (no predilatation) No 13 9 13 Yes 7 9 14 Post dilatation No 7 5 0 Largest stent in LAD (mm), median (IQR) 3.5 (3–3.5) 3.5 (3.5–3.5) 3.5 (3–3.5) Smallest stent in LAD (mm), median (IQR) 3.5 (3–3.5) 3.5 (3–3.5) 3 (2.75–3.5) Total stent length in LAD (mm), median (IQR) 20 (16–20) 29 (26–34) 46 (38–54) Maximum dilatation pressure, median (IQR) 20 (16–20) 20 (16–20) 20 (20–20) IQR �interquartile range. Table 3: Flow indices in relation to total stent length in LAD. Total stent length in LAD 12–22mm n �14 23–37mm n �14 38–78mm n �14 p Before PCI Pa hyperaemia (mm Hg) 82 (65–84) 76 (61–87) 72 (65–88) 0.903 Pd hyperaemia (mm Hg) 58 (45–65) 50.5 (40–67) 49 (41–56) 0.242 FFR 0.77 (0.69–0.80) 0.74 (0.7–0.77) 0.66 (0.46–0.74) 0.002 IMR 20 (11–27) 16 (9–26) 16 (10–20) 0.557 IMR 19 (10–25) 14 (8–24) 14 (10–18) 0.329 corr CFR 2.95 (2.5–3.8) 2.8 (1.5–4.1) 2.15 (1.2–3.8) 0.305 T baseline (seconds) 1.0 (0.65–1.49) 0.72 (0.47–1.37) 0.89 (0.63–1.13) 0.305 mn T hyperaemia (seconds) 0.32 (0.23–0.54) 0.44 (0.2–0.5) 0.32 (0.24–0.42) 0.750 mn After PCI Pa hyperaemia (mm Hg) 72 (64–81) 71 (57–84) 72 (65–80) 0.794 Pd hyperaemia (mm Hg) 64 (55–69) 62 (48–73) 65 (52–72) 0.884 FFR 0.86 (0.84–0.9) 0.84 (0.82–0.87) 0.86 (0.8–0.9) 0.660 IMR 14 (10–17) 15 (9–23) 22 (14–26) 0.118 IMR 13 (10–17) 14 (9–22) 21 (13–25) 0.060 corr CFR 3.6 (2.5–4.9) 3.0 (2–4.7) 2.3 (1.5–4.0) 0.072 T baseline (seconds) 0.85 (0.58–1.31) 0.61 (0.55–0.88) 0.72 (0.52–1.22) 0.824 mn T hyperaemia (seconds) 0.20 (0.17–0.3) 0.21 (0.17–0.36) 0.32 (0.26–0.34) 0.045 mn Median (interquartile range); CFR �coronary flow reserve; FFR �fractional flow reserve; IMR �index of microcirculatory resistance; IMR �corrected corr IMR; Pa �arterial pressure during hyperaemia; Pd �distal pressure during hyperaemia; T �mean transit time; linear regression; variables log-trans- mn formed before analysis. microvascular resistance is attenuated (improved) imme- 4.2. Limitations. +is is an observational study and conclu- diately after PCI [12–14, 34], and these effects seem to persist sions about causal effects cannot be made. +e number of after 10 months of follow-up [12]. Large studies are needed observations is small, and lack of association of IMR and/or to evaluate the natural course of immediate rise of micro- changes in IMR with procedural or baseline characteristics circulatory resistance after stenting, as is the case with variables could be secondary to low power. +e results are subjects with very long total stent length in our study. confined to the LAD only, and effects in the left circumflex or the right coronary artery are not examined. We have not We do know that total stent length is associated with restenosis [35], but the contribution of CMVD in restenosis routinely measured cardiac markers after PCI, and thus we isnotestablished.Inonestudy of29patients,lowercoronary cannot present the frequency of type 4a myocardial infarction. blood flow response to cold-pressor test measured by Assessment of IMR directly after stenting does not reveal if transthoracic Doppler echocardiography (a proxy for alterations of post-PCI IMR are transient or permanent. CMVD) 24 hours after stent implantation in the LAD was +ere are also strengths in this study; all patients in our associated with long-term recurrence of restenosis [8], in- study had stable coronary artery disease only, and the flow dicating that acute coronary microvascular function is im- was assessed before and after PCI in the LAD for all patients. portant in the pathogenesis of restenosis. Large studies are +e patients were all included prospectively before the needed to establish the role of post-PCI CMVD in stable coronary anatomy was known which diminishes the in- coronary artery disease in relation to long-term prognosis. clusion bias inflicted by the perception of the PCI operators. Journal of Interventional Cardiology 5 p interaction = 0.741 p interaction = 0.009 22 4.0 0.90 3.5 0.80 16 3.0 0.70 2.5 0.60 p interaction = 0.013 0 0 0.50 Before PCI Aer PCI 0–22 mm 23–37 mm 38–78 mm 0–22 mm 23–37 mm 38–78 mm Stent length in LAD Before PCI Before PCI 12–22 mm Aer PCI After PCI 23–37 mm 38–78 mm (a) (b) (c) Figure 1: Changes in FFR (a), IMR (b), and CFR (c) before and after PCI in relation to total stent length in LAD. corr 5. Conclusions Conflicts of Interest Changes in IMR during PCI in the LAD in stable CAD seem JP has received grants from Stockholm County Council to be related to total length of stents implanted, possibly (SLL) ALF project, SLL postdoctoral appointment influencing post-PCI FFR. In this study, PCI with very long (20130339), and unrestricted research grants from Abbott total stent length was associated with an immediate rise in Inc. RL is a member of Boston Scientific and Astra Zeneca coronarymicrovascular resistance.Larger studiesareneeded advisory boards. CE, FJ, NOP, NW, HM, MT, and BS have to confirm the relationship between total stent length and no conflicts of interest. changes in IMR during PCI. Acknowledgments Abbreviations +e authors thank Research Nurse Lena Gabrielsson and FFR: Fractional flow reserve staff at Clinical Research Centre North (KFC Norr), Mia OMT: Optimal medical therapy Werner and staff at the elective day care unit, Annika Kinch CMVD: Coronary microvascular dysfunction and staff at the Interventional Catheterization Laboratory, IMR: Index of microcirculatory resistance and Danderyd University Hospital. IMR : Corrected IMR corr CFR: Coronary flow reserve References T : Mean transit time mn P : Proximal coronary pressure [1] N. H. J. Pijls, B. De Bruyne, K. Peels et al., “Measurement of P : Distal coronary pressure fractional flow reserve to assess the functional severity of coronary-artery stenoses,” New England Journal of Medicine, vol. 334, no. 26, pp. 1703–1708, 1996. Data Availability [2] N. H. J. Pijls, P. van Schaardenburgh, G. 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Changes in Index of Microcirculatory Resistance during PCI in the Left Anterior Descending Coronary Artery in Relation to Total Length of Implanted Stents

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Hindawi Journal of Interventional Cardiology Volume 2019, Article ID 1397895, 6 pages https://doi.org/10.1155/2019/1397895 Research Article Changes in Index of Microcirculatory Resistance during PCI in the Left Anterior Descending Coronary Artery in Relation to Total Length of Implanted Stents 1 1 1 Christina Ekenba¨ck, Fadi Jokhaji, Nikolaos Ostlund-Papadogeorgos, 1 1 2 1 1 Habib Mir-Akbari, Rikard Linder, Nils Witt , Mattias To¨rnerud, Bassem Samad, and Jonas Persson Division of Cardiovascular Medicine, Department of Clinical Sciences, Karolinska Institutet, Danderyd University Hospital, Stockholm, Sweden Department of Clinical Science and Education, Karolinska Institutet, Unit of Cardiology, So¨dersjukhuset, Stockholm, Sweden Correspondence should be addressed to Jonas Persson; jonas.persson@sll.se Received 14 August 2019; Revised 4 October 2019; Accepted 14 October 2019; Published 1 December 2019 Academic Editor: Viktor Kocˇka Copyright © 2019 Christina Ekenba¨ck et al. ­is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Aim. To investigate the relationship between stent length and changes in microvascular resistance during PCI in stable coronary artery disease (CAD). Methods and Results. We measured fractional Œow reserve (FFR), index of microcirculatory resistance (IMR), and coronary Œow reserve (CFR) before and after stenting in 42 consecutive subjects with stable coronary artery un- dergoing PCI with stent in the LAD. Patients that had very long stent length (38–78 mm) had lower FFR before stenting than patients that had long (23–37 mm) and moderate (12–22 mm) stent length (0.59 (±0.16), 0.70 (±0.12), and 0.75 (±0.07); p  0.002). FFR improved after stenting and more so in subjects with very long stent length compared to long and moderate stent length (0.27 (s.d ± 16), 0.15 (s.d ± 0.12), and 0.12 (s.d ± 0.07); p for interaction  0.013). Corrected IMR (IMR ) increased after stenting in corr subjects who had very long stent length, whereas IMR was lower after stenting in subjects who had long or moderate stent corr length (4.6 (s.d. ± 10.7), − 1.4 (s.d. ± 9,9), and − 4.2 (s.d. ± 7.8); p for interaction  0.009). Conclusions. Changes in IMR during PCI in the LAD in stable CAD seem to be related to total length of stents implanted, possibly inŒuencing post-PCI FFR. Larger studies are needed to conœrm the relationship. Index of microcirculatory resistance (IMR) is a vali- 1. Introduction dated measurement of coronary microvascular resistance Fractional Œow reserve (FFR) is a validated and reproducible [9], and high IMR (>25 units) can be considered to be a measure of the functional severity of a coronary artery lesion proxy for CMVD [10]. IMR is derived from thermodilu- [1, 2]. FFR-guided PCI with DES and optimal medical tion measurements at peak hyperaemia [9], thereby therapy (OMT) improves outcome and angina symptoms eliminating the variability of coronary resting Œow. Im- for patients with stable coronary artery disease compared to portantly, IMR is measured simultaneously with FFR [11]; OMT alone [3, 4]. Furthermore, higher post-PCI FFR is thus, the physiological signiœcance of epicardial lesions and the coronary microcirculatory function can be con- associated with better outcome [5, 6]. However, increased coronary microvascular resistance is associated with higher currently assessed. post-PCI FFR [7], and coronary microvascular dysfunction Whether epicardial stenosis a¤ects hyperaemic coro- (CMVD) is associated with long-term recurrence of reste- nary microvascular resistance is debated and data are nosis [8]. conŒicting. Studies have shown that PCI lowers 2 Journal of Interventional Cardiology microvascular resistance immediately after stenting [12– used for feasibility (70kg patient receives an infusion of 14], whereas other reports have shown that microvascular 700ml per hour, 80kg patient receives an infusion of 800ml resistance is independent of epicardial lesions [15–18]. +e per hour, and so on.). Furthermore, infusion rates of relationship between stent length and changes in micro- 160–180μg/kg/min are safe and recommended to receive vascular resistance is not known. We hypothesised that maximal hyperaemia [20, 21]. Again, three millilitres of cold there was no improvement, or even impairment, in mi- saline was injected in the LAD three times, and hyperaemic crovascular resistance post-PCI with very long total stent thermodilution curves (Tmn ) and distal (Pd) and prox- hyp length. For this purpose, we measured FFR, IMR, and imal (Pa) coronary pressure were recorded. Measurements coronary flow reserve (CFR) with thermodilution before were repeated after PCI in the LAD in the same position as and after stenting in 42 consecutive subjects with stable before stenting. coronary artery undergoing PCI with stent of the LAD. +e FFR was calculated by dividing Pd by Pa (Pd/Pa) during relationships between changes in coronary flow indices and hyperaemia. CFR was calculated as the ratio between Tmn base total stent length were analysed. and Tmn (Tmn /Tmn ). IMR was calculated as the hyp base hyp product of Tmn and Pd (Tmn ×Pd). IMR can be hyp hyp overestimated in subjects with FFR ≤0.80 due to collateral 2. Methods flow, and thus corrected IMR (IMR ) was calculated corr according to Yong [22]: IMR �Pa ×Tmn ×([1.35 ×Pd/ 2.1.Subjects. Consecutive patients, 18–85 years of age, with corr hyp Pa] − 0.32). an life expectancy of >2 years that were planned for coronary angiography due to stable coronary artery disease nd th were included between 2 of September 2015 and 20 of 2.3. Statistics. Median values and interquartile range (IQR) September 2017. Subjects were included before coronary are presented for continuous variables. Numbers and pro- anatomy was known. Patients with acute coronary syn- portions are presented for categorical variables. Stent length drome, congestive heart failure with ejection fraction was categorized into three different categories since the <39%, prior heart transplantation, prior coronary artery variable is ordinal and non-normally distributed; moderate by-pass grafting, hypertrophic cardiomyopathy, valvular (12–22mm), long (23–37mm), and very long (38–78mm) heart disease scheduled for surgery/intervention, cancer stent length. Linear regression was used to compare flow within three years of admission, peri- and/or myocarditis, indices between groups. Two-way repeated measures contrast allergy, atrial fibrillation with ventricular rate ANOVA analyses (Wilks-Lambda) were used to analyse >120, asthma bronchiale, and atrioventricular block II-III changes inIMR andCFR beforeandafterstenting inrelation were excluded. After coronary angiography, measure- to stent length group. Non-normally distributed variables, ments of FFR, CFR, and IMR in the LAD were conducted including IMR , were log-transformed before analysis. α corr irrespectively of coronary anatomy. Subjects with chronic was two-sided and set to 0.05. IBM SPSS Statistics 23.0 was total occlusion in the LAD, heavy calcification, or tortu- used for analyses. osity in the left main/LAD hindering safe passage of a guide-wire with pressure and temperature sensors were excluded at the discretion of the PCI operator. In total, 274 3. Results subjects were included after oral and written informed 3.1. Baseline Procedural Characteristics. Forty-two patients consent was obtained. In the current analysis, we report underwent stenting of the LAD and had flow indices pre- to post-PCI changes in FFR, CFR, and IMR in relation measured before and after stenting. Seven patients were to total stent length and other variables in subjects treated women, seven had diabetes mellitus, and two thirds of the with PCI in the LAD who had flow indices measured both patients had one-vessel disease (Table 1). A majority (90%) before and after PCI (n �42). Ethical permission was of the patients had Canadian Cardiovascular Society grade I approved by the Regional Ethical Review Board in and II angina pectoris. All patients were stented with Stockholm (no 2015/962–31). second generation drug-eluting stent (everolimus, n �23; zotarolimus, n �13; sirolimus, n �6). One patient in the 2.2. Flow Measurements. FFR, IMR, and CFR were mea- long stent length group (23–37mm) received a bio- sured in the LAD after initial coronary angiography and degradable vascular scaffold, and one patient in the very again after PCI of the LAD. A coronary guide-wire with long stent length group (38–78mm) was stented also in the pressure and temperature sensors (Pressure Wire X; Abbott left main. All patients were on double antiplatelet therapy. Inc., CA, USA) was advanced in the LAD (sensors>70mm Two patients were on ticagrelor, of which one was a non- from the catheter tip and distal to the lesion). +ree mil- responder to clopidogrel (Multiplate ADPtest) and the lilitres of cold saline was injected into the LAD, and ther- other patient was allergic to clopidogrel. A few (n �4) modilution curves were recorded. +e procedure was lesions were treated by direct stenting, a majority of the repeated in total three times calculating the mean transit stents were post-dilated (Table 2), and no debulking devices time (Tmn ). +en, adenosine (dosage of 167μg/kg/min) such as rotational atherectomy were used. Patients that had base was administered intravenously in a large cubital vein for very long stent length had lower FFR before stenting and two minutes to induce stable hyperaemia. A higher infusion higher Tmn after stenting than the other two groups hyp rate of adenosine 1mg/ml than in other studies [19, 20] was (Table 3). Journal of Interventional Cardiology 3 Table 1: Baseline characteristics. microcirculation after the procedure (on average 4.6 units IMR -change from pre-to post-PCI). Age, years (s.d.) 65.3 (8.2) corr Female gender, n (%) 7 (17) Total stent length can be considered to be a proxy for both Diabetes mellitus, n (%) 7 (17) atherosclerotic burden and complexity of PCI procedures. In Previous myocardial infarction, n (%) 5 (12) more complex PCI with very long total stent length, more Previous PCI, n (%) 9 (21) balloon dilatations, and interactions with a larger part of the Atrial flutter, n (%) 2 (5) vessel wall, the occurrence of impaired microcirculation and Smoking, n (%) rise in the resistance are likely more frequent than in less Never 24 (57) complex PCI, which explain our findings with elevated IMR Previous 13 (31) after PCI with very long stent length. Supporting this, is a Smoker 5 (12) randomized trial of direct stenting compared to stenting with Canadian Cardiovascular Society grade, n (%) predilatation (more complex technique), indicating that di- I 15 (36) rect stenting with fewer dilatations is less traumatic for the II 23 (55) coronary microcirculation as compared to conventional III 3 (7) stenting [23]. Elective PCI might impair resting microvas- IV 1 (2) cular perfusion [24] through several different mechanisms Body mass index (kg/m ), median (IQR) 27 (24–30) acutely elevating the coronary microcirculatory resistance; Total cholesterol (mmol/L), median (IQR) 4.3 (3.7–5.1) release of local vasoconstrictors [25], vasoconstriction [26], Low density lipoprotein cholesterol (mmol), 2.4 (1.9–3.1) impairment of endothelial function [27, 28], and distal em- median (IQR) HbA c (mmol/mol), median (IQR) 39 (35–42) bolization [29, 30]. Microvascular impairment is more likely Creatinine clearance (mL/min/1.73m ), median tooccurduringmorecomplexPCIand/orinverylonglesions 82 (69–96) (IQR) than in less complex interventions. Medication at inclusion Coronary microvascular disease is one of the limitations Aspirin 42 (100) when identifying ischemic lesions with FFR [21]. It is dif- Clopidogrel 40 (95) ficult to appreciate the effects of immediate (and possibly Ticagrelor 2 (5) transient) acute rise in coronary microcirculation resistance AII-receptor antagonists, n (%) 12 (29) corresponding to 4.6 units IMR on distal pressure in the corr Beta-blockers, n (%) 26 (62) LAD (P ) and subsequent elevation of FFR values after PCI. Nitrates, n (%) 10 (24) Studies have consistently shown that higher FFR values after Calcium antagonists, n (%) 13 (31) stenting is associated with lower MACE rates [5, 6, 31, 32]. A ACE inhibitors, n (%) 9 (21) recent meta-analysis of post-PCI FFR measurements in Lipid-lowering therapy at admission 32 (76) FAME-1 and FAME-2 showed that the best cut-off value for IQR �interquartile range. predicting two-year vessel-oriented composite endpoint (death, MI, revascularization) was 0.915, with a sensitivity of 3.2.ChangesinFlowIndices. Asexpected, FFR wasimproved 75% and specificity of 43%. However, the authors conclude after stenting and more so in subjects with very long stent that its predictive value is too low for optimization of PCI length (p for interaction �0.013; Figure 1(a)). Changes in procedures [32]. Assessing FFR in combination with post- IMR were related to stent length in LAD; IMR in- corr corr PCI IMR provides information about the treated epicardial creased after stenting in subjects who had very long stent lesion and the microcirculatory function immediately after length (38–78mm), whereas IMR was attenuated after corr the intervention. +is might improve sensitivity, specificity, stenting in subjects who had moderate or long (12–22mm and predictive value for future major adverse cardiovascular and 23–37mm, respectively) stent length (p for inter- events. +e interpretation of post-PCI FFR may benefit from action �0.009; Figure 1(b)). Changes in CFR were not re- concurrent assessment of the coronary microcirculation, but lated to stent length (Figure 1(c)). it needs to be evaluated in studies. Pre-PCI IMR is associated with post-PCI in a several 4. Discussion studies [12, 33, 34]. In our study, pre-PCI IMR are accounted 4.1. Implications. Our data shows that PCI with very long for in the analysis since we are studying changes in IMR stent length (≥38mm) in the LAD is associated with larger during PCI. Diabetes mellitus is associated with post-PCI IMR in a small study mixing acute coronary syndromes and improvement in FFR than in moderate or long stent length. +eimprovementinFFRwasaccompaniedbyariseinIMR stable coronary artery disease [33]. Diabetes mellitus was not corr an interaction term for changes in IMR in our study (data after stenting for very long stent length, whereas moderate and long stent length was associated with attenuated IMR . not shown), possibly due to low power with only seven corr +e findings have two important implications: (i) PCI subjects with diabetes mellitus. with very long total stent length in patients with stable In experimental human and animal studies, assessment coronary artery disease in the elective setting is associated of IMR is independent of artificial stenosis created by bal- with a rise in resistance after PCI in the coronary micro- loons and a vascular occluder [17, 18], and studies of IMR circulation and (ii) improved FFR values after PCI with very before and after PCI have shown that there are no alterations long total stent length may be partly explained by the im- in microvascular resistance when collateral flow is taken into mediate rise in the resistance of the coronary account [15, 16]. However, other studies have shown that 4 Journal of Interventional Cardiology Table 2: Procedural characteristics. Total stent length in LAD 12–22mm 23–37mm 38–78mm n �14 n �14 n �14 1 14 9 5 Number of stents in LAD 2 0 5 7 3 0 0 2 Yes 1 3 0 Direct stenting (no predilatation) No 13 9 13 Yes 7 9 14 Post dilatation No 7 5 0 Largest stent in LAD (mm), median (IQR) 3.5 (3–3.5) 3.5 (3.5–3.5) 3.5 (3–3.5) Smallest stent in LAD (mm), median (IQR) 3.5 (3–3.5) 3.5 (3–3.5) 3 (2.75–3.5) Total stent length in LAD (mm), median (IQR) 20 (16–20) 29 (26–34) 46 (38–54) Maximum dilatation pressure, median (IQR) 20 (16–20) 20 (16–20) 20 (20–20) IQR �interquartile range. Table 3: Flow indices in relation to total stent length in LAD. Total stent length in LAD 12–22mm n �14 23–37mm n �14 38–78mm n �14 p Before PCI Pa hyperaemia (mm Hg) 82 (65–84) 76 (61–87) 72 (65–88) 0.903 Pd hyperaemia (mm Hg) 58 (45–65) 50.5 (40–67) 49 (41–56) 0.242 FFR 0.77 (0.69–0.80) 0.74 (0.7–0.77) 0.66 (0.46–0.74) 0.002 IMR 20 (11–27) 16 (9–26) 16 (10–20) 0.557 IMR 19 (10–25) 14 (8–24) 14 (10–18) 0.329 corr CFR 2.95 (2.5–3.8) 2.8 (1.5–4.1) 2.15 (1.2–3.8) 0.305 T baseline (seconds) 1.0 (0.65–1.49) 0.72 (0.47–1.37) 0.89 (0.63–1.13) 0.305 mn T hyperaemia (seconds) 0.32 (0.23–0.54) 0.44 (0.2–0.5) 0.32 (0.24–0.42) 0.750 mn After PCI Pa hyperaemia (mm Hg) 72 (64–81) 71 (57–84) 72 (65–80) 0.794 Pd hyperaemia (mm Hg) 64 (55–69) 62 (48–73) 65 (52–72) 0.884 FFR 0.86 (0.84–0.9) 0.84 (0.82–0.87) 0.86 (0.8–0.9) 0.660 IMR 14 (10–17) 15 (9–23) 22 (14–26) 0.118 IMR 13 (10–17) 14 (9–22) 21 (13–25) 0.060 corr CFR 3.6 (2.5–4.9) 3.0 (2–4.7) 2.3 (1.5–4.0) 0.072 T baseline (seconds) 0.85 (0.58–1.31) 0.61 (0.55–0.88) 0.72 (0.52–1.22) 0.824 mn T hyperaemia (seconds) 0.20 (0.17–0.3) 0.21 (0.17–0.36) 0.32 (0.26–0.34) 0.045 mn Median (interquartile range); CFR �coronary flow reserve; FFR �fractional flow reserve; IMR �index of microcirculatory resistance; IMR �corrected corr IMR; Pa �arterial pressure during hyperaemia; Pd �distal pressure during hyperaemia; T �mean transit time; linear regression; variables log-trans- mn formed before analysis. microvascular resistance is attenuated (improved) imme- 4.2. Limitations. +is is an observational study and conclu- diately after PCI [12–14, 34], and these effects seem to persist sions about causal effects cannot be made. +e number of after 10 months of follow-up [12]. Large studies are needed observations is small, and lack of association of IMR and/or to evaluate the natural course of immediate rise of micro- changes in IMR with procedural or baseline characteristics circulatory resistance after stenting, as is the case with variables could be secondary to low power. +e results are subjects with very long total stent length in our study. confined to the LAD only, and effects in the left circumflex or the right coronary artery are not examined. We have not We do know that total stent length is associated with restenosis [35], but the contribution of CMVD in restenosis routinely measured cardiac markers after PCI, and thus we isnotestablished.Inonestudy of29patients,lowercoronary cannot present the frequency of type 4a myocardial infarction. blood flow response to cold-pressor test measured by Assessment of IMR directly after stenting does not reveal if transthoracic Doppler echocardiography (a proxy for alterations of post-PCI IMR are transient or permanent. CMVD) 24 hours after stent implantation in the LAD was +ere are also strengths in this study; all patients in our associated with long-term recurrence of restenosis [8], in- study had stable coronary artery disease only, and the flow dicating that acute coronary microvascular function is im- was assessed before and after PCI in the LAD for all patients. portant in the pathogenesis of restenosis. Large studies are +e patients were all included prospectively before the needed to establish the role of post-PCI CMVD in stable coronary anatomy was known which diminishes the in- coronary artery disease in relation to long-term prognosis. clusion bias inflicted by the perception of the PCI operators. Journal of Interventional Cardiology 5 p interaction = 0.741 p interaction = 0.009 22 4.0 0.90 3.5 0.80 16 3.0 0.70 2.5 0.60 p interaction = 0.013 0 0 0.50 Before PCI Aer PCI 0–22 mm 23–37 mm 38–78 mm 0–22 mm 23–37 mm 38–78 mm Stent length in LAD Before PCI Before PCI 12–22 mm Aer PCI After PCI 23–37 mm 38–78 mm (a) (b) (c) Figure 1: Changes in FFR (a), IMR (b), and CFR (c) before and after PCI in relation to total stent length in LAD. corr 5. Conclusions Conflicts of Interest Changes in IMR during PCI in the LAD in stable CAD seem JP has received grants from Stockholm County Council to be related to total length of stents implanted, possibly (SLL) ALF project, SLL postdoctoral appointment influencing post-PCI FFR. In this study, PCI with very long (20130339), and unrestricted research grants from Abbott total stent length was associated with an immediate rise in Inc. RL is a member of Boston Scientific and Astra Zeneca coronarymicrovascular resistance.Larger studiesareneeded advisory boards. CE, FJ, NOP, NW, HM, MT, and BS have to confirm the relationship between total stent length and no conflicts of interest. changes in IMR during PCI. Acknowledgments Abbreviations +e authors thank Research Nurse Lena Gabrielsson and FFR: Fractional flow reserve staff at Clinical Research Centre North (KFC Norr), Mia OMT: Optimal medical therapy Werner and staff at the elective day care unit, Annika Kinch CMVD: Coronary microvascular dysfunction and staff at the Interventional Catheterization Laboratory, IMR: Index of microcirculatory resistance and Danderyd University Hospital. IMR : Corrected IMR corr CFR: Coronary flow reserve References T : Mean transit time mn P : Proximal coronary pressure [1] N. H. J. Pijls, B. De Bruyne, K. Peels et al., “Measurement of P : Distal coronary pressure fractional flow reserve to assess the functional severity of coronary-artery stenoses,” New England Journal of Medicine, vol. 334, no. 26, pp. 1703–1708, 1996. Data Availability [2] N. H. J. Pijls, P. van Schaardenburgh, G. 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