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Detection of left coronary ostial obstruction during transcatheter aortic valve replacement by coronary flow velocity measurement in the left main trunk by intraoperative transesophageal echocardiography

Published:September 14, 2022DOI:https://doi.org/10.1016/j.jjcc.2022.08.009

      Highlights

      • Left coronary artery (LCA) obstruction is an often hard-to-detect transcatheter aortic valve replacement (TAVR) complication.
      • The flow velocity in left main trunk were measured by transesophageal echocardiography before and after valve implantation.
      • The blood flow accelerated in the LCA obstruction patients after valve implantation.
      • The post/pre-TAVR velocity ratios were >2.0 in all stable LCA obstruction patients.
      • The intraprocedural measurement of flow velocity is useful for detecting LCA obstruction.

      Abstract

      Background

      Coronary obstruction is a rare but catastrophic complication of transcatheter aortic valve replacement (TAVR) and occurs mostly at the left coronary artery (LCA) ostium. However, some patients do not show any clinical findings, and thus, its detection is sometimes difficult. The peak diastolic flow velocity in left main coronary artery (LM) was reportedly increased in significant stenosis lesions. We evaluated the effectiveness of measuring blood flow velocities in LM by transesophageal echocardiography (TEE) for the detection of LCA ostial obstruction during a TAVR procedure.

      Methods

      A total of 1105 consecutive patients who underwent TAVR in Sendai Kousei Hospital between September 2014 and December 2020 were enrolled. The LM blood flow velocity was measured at pre- and post-valve implantation.

      Results

      Among the 1105 patients, 9 had LCA ostial obstruction. The peak LM blood flow velocity at post-TAVR [0.90 (0.39–1.15) vs. 0.37 (0.28–0.50) m/s; p = 0.0046) was significantly higher in 9 patients who had LCA ostial obstruction, compared with the remaining 1096 patients who had not (controls), although no significant difference was observed before the TAVR procedures between the two groups. The post- to pre-TAVR LM flow velocity ratio [2.26 (1.31–3.42) vs. 1.06 (0.82–1.36); p = 0.0030] was also significantly higher in patients with LCA obstruction, compared to the controls. Furthermore, the post- to pre-TAVR LM blood flow velocity ratio was >2.0 in all six hemodynamically stable patients with LCA obstruction, whereas <2.0 in all three patients with LCA obstruction who showed hemodynamic collapse at post-TAVR procedure.

      Conclusion

      Coronary blood flow velocity in LM significantly increased in hemodynamically stable LCA obstruction patients. The intraprocedural TEE measurement of the LM flow velocities would be potentially useful to detect asymptomatic and hemodynamically stable LCA ostial obstruction.

      Graphical abstract

      Keywords

      Abbreviations:

      TAVR (transcatheter aortic valve replacement), AS (aortic stenosis), SAVR (surgical aortic valve replacement), ACC (American College of Cardiology), LCA (left coronary artery), LM (left main coronary artery), CT (computed tomography), AOG (aortography), CAG (coronary angiography), THV (transcatheter heart valve)

      Introduction

      Transcatheter aortic valve replacement (TAVR) has become a safe and effective treatment option for severe aortic stenosis (AS) in patients who are prohibitively, highly, or intermediately at risk for surgical aortic valve replacement (SAVR) [
      • Leon M.B.
      • Smith C.R.
      • Mack M.
      • Miller D.C.
      • Moses J.W.
      • Svensson L.G.
      • et al.
      Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery.
      ,
      • Leon M.B.
      • Smith C.R.
      • Mack M.J.
      • Makkar R.R.
      • Svensson L.G.
      • Kodali S.K.
      • et al.
      Transcatheter or surgical aortic-valve replacement in intermediate-risk patients.
      ,
      • Adams D.H.
      • Popma J.J.
      • Reardon M.J.
      • Yakubov S.J.
      • Coselli J.S.
      • Deeb G.M.
      • et al.
      Transcatheter aortic-valve replacement with a self-expanding prosthesis.
      ,
      • Reardon M.J.
      • Van Mieghem N.M.
      • Popma J.J.
      • Kleiman N.S.
      • Søndergaard L.
      • Mumtaz M.
      • et al.
      Surgical or transcatheter aortic-valve replacement in intermediate-risk patients.
      ]. Moreover, recent trials have demonstrated the safety and efficacy of TAVR in low-risk patients [
      • Mack M.J.
      • Leon M.B.
      • Thourani V.H.
      • Makkar R.
      • Kodali S.K.
      • Russo M.
      • et al.
      Transcatheter aortic-valve replacement with a balloon-expandable valve in low-risk patients.
      ,
      • Popma J.J.
      • Deeb G.M.
      • Yakubov S.J.
      • Mumtaz M.
      • Gada H.
      • O'Hair D.
      • et al.
      Transcatheter aortic-valve replacement with a self-expanding valve in low-risk patients.
      ]. In the American College of Cardiology (ACC)/American Heart Association guideline 2020, both TAVR and SAVR are recommended equally even in patients with symptomatic severe AS aged 65–80 years. Furthermore, TAVR is recommended for patients with asymptomatic severe AS with a left ventricular ejection fraction of <50 % in preference to SAVR [
      • Otto C.M.
      • Nishimura R.A.
      • Bonow R.O.
      • Carabello B.A.
      • Erwin III, J.P.
      • Gentile F.
      • et al.
      2020 ACC/AHA guideline for the management of patients with valvular heart disease: a report of the american College of Cardiology/American Heart Association joint committee on clinical practice guidelines.
      ]. However, TAVR still has a risk of serious complications, such as coronary obstruction. Previous studies have shown that such complications are rare but often associated with a high mortality rate [
      • Ribeiro H.B.
      • Webb J.G.
      • Makkar R.R.
      • Cohen M.G.
      • Kapadia S.R.
      • Kodali S.
      • et al.
      Predictive factors, management, and clinical outcomes of coronary obstruction following transcatheter aortic valve implantation: insights from a large multicenter registry.
      ]. Coronary obstruction mostly occurs at the left coronary artery (LCA) ostium and commonly represents symptoms, such as severe persistent hypotension, ST-segment changes in electrocardiography, and ventricular arrhythmia [
      • Ribeiro H.B.
      • Webb J.G.
      • Makkar R.R.
      • Cohen M.G.
      • Kapadia S.R.
      • Kodali S.
      • et al.
      Predictive factors, management, and clinical outcomes of coronary obstruction following transcatheter aortic valve implantation: insights from a large multicenter registry.
      ,
      • Ribeiro H.B.
      • Nombela-Franco L.
      • Urena M.
      • Mok M.
      • Pasian S.
      • Doyle D.
      • et al.
      Coronary obstruction following transcatheter aortic valve implantation: a systematic review.
      ]. However, sometimes these symptoms are absent [
      • Ribeiro H.B.
      • Nombela-Franco L.
      • Urena M.
      • Mok M.
      • Pasian S.
      • Doyle D.
      • et al.
      Coronary obstruction following transcatheter aortic valve implantation: a systematic review.
      ,
      • Higuchi R.
      • Mahara K.
      • Naito K.
      • Takamisawa I.
      • Shimizu J.
      • Iguchi N.
      • et al.
      Silent coronary obstruction following transcatheter aortic valve implantation: detection by transesophageal echocardiography.
      ]. Therefore, acute coronary obstruction during the TAVR procedure may be missed in cases of delayed occlusion because some difficulties are encountered in assessing coronary ostial subtotal occlusion using angiography alone in some cases [
      • Higuchi R.
      • Mahara K.
      • Naito K.
      • Takamisawa I.
      • Shimizu J.
      • Iguchi N.
      • et al.
      Silent coronary obstruction following transcatheter aortic valve implantation: detection by transesophageal echocardiography.
      ,
      • Jabbour R.J.
      • Tanaka A.
      • Finkelstein A.
      • Mack M.
      • Tamburino C.
      • Van Mieghem N.
      • et al.
      Delayed coronary obstruction after transcatheter aortic valve replacement.
      ]. Thus, other imaging or physiological assessment modalities are necessary to detect coronary ostial obstruction during TAVR.
      Several reports have shown that measurement of coronary blood flow velocity was useful to detect significant coronary artery stenosis because flow velocities in a stenotic site are stronger than those in a non-stenotic site [
      • Anjaneyulu A.
      • Raghu K.
      • Chandramukhi S.
      • Satyajit G.M.
      • Arramraja S.
      • Raghavaraju P.
      • et al.
      Evaluation of left main coronary artery stenosis by transthoracic echocardiography.
      ,
      • Krzanowski M.
      • Bodzoń W.
      • Brzostek T.
      • Nizankowski R.
      • Szczeklik A.
      Value of transthoracic echocardiography for the detection of high-grade coronary artery stenosis: prospective evaluation in 50 consecutive patients scheduled for coronary angiography.
      ,
      • Hozumi T.
      • Yoshida K.
      • Akasaka T.
      • Asami Y.
      • Kanzaki Y.
      • Ueda Y.
      • et al.
      Value of acceleration flow and the prestenotic to stenotic coronary flow velocity ratio by transthoracic color doppler echocardiography in noninvasive diagnosis of restenosis after percutaneous transluminal coronary angioplasty.
      ,
      • Saraste M.
      • Vesalainen R.K.
      • Ylitalo A.
      • Saraste A.
      • Koskenvuo J.W.
      • Toikka J.O.
      • et al.
      Transthoracic doppler echocardiography as a noninvasive tool to assess coronary artery stenoses - a comparison with quantitative coronary angiography.
      ,
      • Yasu T.
      • Yamagishi M.
      • Beppu S.
      • Nagata S.
      • Miyatake K.
      Left main coronary flow velocity associated with stenosis. Evaluation by transesophageal color-guided pulsed doppler technique.
      ,
      • Yamagishi M.
      • Yasu T.
      • Ohara K.
      • Kuro M.
      • Miyatake K.
      Detection of coronary blood flow associated with left main coronary artery stenosis by transesophageal doppler color flow echocardiography.
      ]. The peak diastolic flow velocity in the left main coronary artery (LM) was reportedly higher when significant stenosis was present, as compared with when it was absent [
      • Yasu T.
      • Yamagishi M.
      • Beppu S.
      • Nagata S.
      • Miyatake K.
      Left main coronary flow velocity associated with stenosis. Evaluation by transesophageal color-guided pulsed doppler technique.
      ,
      • Yamagishi M.
      • Yasu T.
      • Ohara K.
      • Kuro M.
      • Miyatake K.
      Detection of coronary blood flow associated with left main coronary artery stenosis by transesophageal doppler color flow echocardiography.
      ]. Therefore, increased blood flow velocity in the LM detected by intraoperative transesophageal echocardiography (TEE) was hypothesized to be a sign of LCA ostial obstruction after a transcatheter heart valve implantation. In the current study, pre- and post-TAVR peak diastolic velocities in the LM were measured in consecutive patients undergoing TAVR, and the rationality of measurements was assessed to detect LCA ostial obstruction.

      Methods

      Study population

      A total of 1159 consecutive patients with severe AS underwent TAVR at Sendai Kosei Hospital between September 2014 and December 2020. Patients who had undergone coronary artery bypass grafting (CABG) and/or those with missing data of flow velocity measurements in the LM during TAVR were excluded. The strategy for the TAVR procedure was decided based on the consensus of a dedicated heart team, which included experienced interventional cardiologists and cardiovascular surgeons. The current study complied with the Declaration of Helsinki and was approved by the ethics committee of Sendai Kousei Hospital. Written informed consent was obtained from all patients.

      TAVR procedure

      TAVR procedures were conducted under general anesthesia with fluoroscopic and TEE guidance. While approaching the site, TAVR valve type and size were determined by the heart team in Sendai Kousei Hospital following the preprocedural assessment of computed tomography (CT). Coronary artery protection using guiding catheters, guide wires, and balloons for percutaneous coronary intervention (PCI) was conducted in patients highly at risk of coronary obstruction, such as the low origin of the coronary arteries and smaller diameters of Valsalva sinus or sino-tubular junction [
      • Ribeiro H.B.
      • Webb J.G.
      • Makkar R.R.
      • Cohen M.G.
      • Kapadia S.R.
      • Kodali S.
      • et al.
      Predictive factors, management, and clinical outcomes of coronary obstruction following transcatheter aortic valve implantation: insights from a large multicenter registry.
      ]. The peak coronary flow velocities in the LM and blood pressures were recorded at pre-TAVR procedure and immediately after the transcatheter heart valve placement.

      How to visualize coronary blood flow and measure flow velocity by TEE

      Three experienced sonographers, YS, YM, and MS, conducted TEE-based measurements of the LM flow velocities pre- and post-TAVR procedure using iE33 and X7-2t or X8-2t probe (Philips, Amsterdam, Netherlands) (Fig. 1). The LM was visualized in the left ventricular outflow view, and the scan angle between 90° and 120° was adjusted to align the ultrasound beam as parallel to LM blood flow as possible. When the LM was visualized, colored images of the coronary blood flow were obtained. The velocity range was set in the range of ± 15.0 to 20.0 cm/s. The color gain was adjusted to provide optimal images. The pulse-wave Doppler was used to record coronary flow velocity signals. The measurement was obtained in one cardiac cycle. The pre- to post-TAVR velocity ratio was calculated. After November 2017, the measurement was also conducted after the revascularization for LM obstruction.
      Fig. 1
      Fig. 1Transthoracic echocardiographic image to measure the flow velocity in the left main coronary artery during a transcatheter aortic valve replacement procedure.

      Diagnosis of LM ostial obstruction

      The diagnosis of LCA ostial obstruction was made based on the Valve Academic Research Consortium-2 consensus document (VARC-2) criteria [
      • Kappetein A.P.
      • Head S.J.
      • Généreux P.
      • Piazza N.
      • van Mieghem N.M.
      • Blackstone E.H.
      • et al.
      Updated standardized endpoint definitions for transcatheter aortic valve implantation: the valve academic research Consortium-2 consensus document (VARC-2).
      ]. The document stated that coronary obstruction is diagnosed by angiographic or echocardiographic evidence of a new, partial, or complete, obstruction of a coronary ostium, either by the valve prosthesis itself, the native leaflets, calcifications, or dissection, occurring during or after the TAVI procedure. In our clinical practice, aortography (AOG) was conducted in all the TAVR cases except for patients with severe chronic kidney disease. When LCA obstruction could be excluded by AOG, coronary angiography (CAG) was not performed. If LCA ostial obstruction is suspected or could not be clearly ruled out, CAG was performed. When CAG showed the evidence defined in the VARC-2 criteria, we diagnosed LCA ostial obstruction.

      Analyses

      Patients were divided into two groups with and without LCA ostial obstruction. The peak diastolic blood flow velocity in the LM was compared between the two groups. Furthermore, the post- to pre-TAVR peak velocity ratio was also compared. In patients with LCA obstruction, a relationship between coronary blood flow velocity and blood pressure was also assessed.

      Statistical analysis

      All statistical analyses were conducted using JMP 14.3.0 software (SAS Institute, Inc., Cary, NC, USA). Continuous variables are presented as medians and interquartile range. Mann-Whitney U test was used to assess for significant differences on continuous variables. Chi-squared test was used for comparing categorical variables. A p-value of <0.05 indicated statistical significance.

      Results

      Baseline characteristics and procedural variables

      Among the 1159 consecutive patients who underwent TAVR, the following patients were excluded from analyses: 1) those who underwent CABG to the left anterior descending branch and/or left circumflex branch (n = 34); 2) those who received TEE guidance during the TAVI procedure (n = 8); 3) those in whom blood flow velocities could not be measured because of procedural complications, such as rupture or cardiac tamponade (n = 12). Data of the remaining 1105 patients were analyzed, and their flow velocity data were obtained. Patient characteristics, including echocardiographic data, preprocedural CT data, procedural variables, and clinical outcomes, are shown in Table 1. Balloon-expandable transcatheter heart valve was selected in 911 (82.4 %) patients. The transfemoral approach was selected in 1072 patients (97.0 %) (Table 1).
      Table 1Baseline characteristics and procedural variables.
      Overall (n = 1105)LCA obstruction (n = 9)Controls (n = 1096)P value
      Clinical characteristics
       Age, years84 (80–87)88 (85–92)84 (80–87)0.012
       Male, n (%)378 (34.2)1(11.1)377 (34.4)0.029
       Weight, kg52.3 (45.0–60.2)47.9 (38–51.0)52.5 (45.0–60.5)0.045
       Height, cm150 (145–158)142 (139–154)150 (145–158)0.020
       BSA, m21.47 (1.35–1.61)1.37 (1.21–1.44)1.47 (1.35–1.61)0.020
       STS score, %6.0 (4.2–9.8)7.6 (3.6–9.7)6.0 (4.2–9.8)0.806
      Echocardiographic data
       Mean pressure gradient, mm Hg51 (39–64)63 (48–73)50 (39–64)0.139
       Aortic valve area, cm20.72 (0.60–0.86)0.62 (0.51–0.85)0.73 (0.60–0.86)0.250
       Peak velocity, m/s4.6 (4.1–5.1)5.2 (5.0–5.4)4.6 (4.1–5.1)0.022
       Left ventricular ejection fraction, %53 (44–60)61 (51–77)53 (44–60)0.054
       Aortic regurgitation ≥ moderate, n (%)269 (24.3)3 (33.3)266 (24.3)0.523
      Pre-procedural computed tomography data
       Annular area, mm2411 (366–471)395 (341–518)411 (366–471)0.628
      Aortic annular perimeter, mm73.5 (69.2–78.6)71.4 (66.4–81.2)73.6 (69.2–78.6)0.513
      Sinus of Valsalva diameter, mm
      LCC30.0 (27.8–32.8)28.9 (25.5–30.7)30.1 (27.8–32.8)0.101
      RCC29.3 (27.3–32.0)29.3 (26.2–30.1)29.4 (27.3–32.0)0.300
      NCC30.8 (28.6–33.5)30.2 (27.2–32.1)30.8 (28.6–33.5)0.272
      Bicuspid, n (%)86 (7.8)0 (0.0)86 (7.8)1.000
      Height of coronary artery, mm
      Left13.8 (12.4–15.3)12.1 (9.8–13.1)13.8 (12.4–15.3)0.002
      Right15.3 (13.5–17.3)13.9 (11.6–14.3)15.3 (13.5–17.3)0.023
      Procedural variables
       Approach, n (%)
      Transfemoral1072 (97.0)9 (100)1063 (97.0)0.603
      Transapical24 (2.2)0 (0.0)24 (2.2)0.654
      Transsubcravian5 (0.5)0 (0.0)5 (0.5)0.839
      Direct aortic3 (0.3)0 (0.0)3 (0.3)0.875
       Valve, n (%)
      Balloon-expandable911 (82.4)7 (77.7)904 (82.5)0.712
      Self-expandable194 (17.6)2 (22.2)192 (17.5)0.712
       Post-dilatation, n (%)490 (44.3)3 (33.3)487 (44.4)0.504
       Coronary protection, n (%)31 (2.8)1 (11.1)30 (2.7)0.131
       Selective coronary angiography, n (%)49 (4.4)9 (100)40 (3.7)<0.001
       THV embolization, n (%)0 (0.0)0 (0.0)0 (0.0)
       Coronary occlusion, n (%)
      Left9 (0.9)9 (100)0 (0.0)
      Right1 (0.1)0 (0.0)1 (0.1)0.928
       Annular rupture, n (%)3 (0.3)0 (0.0)3 (0.3)0.875
      Values are median (interquartile range) or n (%).
      BSA, body surface area; STS, Society of Thoracic Surgeons; LCC, left coronary cusp; RCC, right coronary cusp; NCC, non-coronary cusp; THV, transcatheter heart valve.
      Among the 1105 patients who qualified for analysis, 9 had LCA ostial obstruction (0.9 %) and successfully underwent rescue coronary revascularization (PCI in 8 and CABG in 1) (Table 2). Comparisons of patient characteristics between the 9 patients with LCA ostial obstruction and the remaining 1096 patients who did not experience LCA obstruction (controls), including a patient who experienced RCA obstruction, are also shown in Table 1.
      Table 2List of patients with LCA obstruction after TAVR.
      NoAgeSexValveCoronary revascularizationBlood flow velocity in LM, m/sPost- to pre-TAVR LM blood flow velocity ratioSystolic/diastolic BP, mm HgHemodynamic support
      Pre-TAVRPost-TAVRPost-revascularizationPre-TAVRPost-TAVR
      196FSAPIEN XTPCI0.260.13N/A0.50126/4857/27Positive innotropic agents, PCPS
      290FSAPIEN XTPCI0.190.43N/A2.26103/3697/35
      393FSAPIEN 3PCI0.271.13N/A4.19112/46122/47
      479FEvolut RCABG0.41.26N/A3.15120/54N/A
      591FEvolut RPCI0.380.690.501.82161/4287/42Positive innotropic agents, PCPS
      684FSAPIEN 3PCI0.331.160.383.52121/55104/47
      787FSAPIEN 3PCI0.270.900.213.33128/52122/47
      888FSAPIEN 3PCI0.491.000.452.04173/68136/49
      986MSAPIEN 3PCI0.430.340.220.7996/3764/25Positive innotropic agents, PCPS
      LCA, left coronary artery; LM, left main coronary artery; TAVR, transcatheter aortic valve replacement; BP, blood pressure; PCI, percutaneous coronary intervention; CABG, coronary artery bypass grafting; IABP, intra-aortic balloon pumping; PCPS, percutaneous cardiopulmonary support.

      Comparison of flow velocity in the LM between the two groups

      The peak blood flow velocity in the LM was compared between patients with LCA ostial obstruction and controls. No significant differences were observed in the LM flow velocity at pre-TAVI procedure between the two groups: LCA obstruction and control [0.33 (0.27–0.42) and 0.35 (0.26–0.46) m/s, respectively] (Fig. 2A ). In contrast, the LM flow velocity at post-TAVR was higher in the LCA obstruction group than that in the control group [0.90 (0.39–1.14) vs. 0.37 (0.28–0.50) m/s; p = 0.0046]. The post- to pre-TAVR LM flow velocity ratio was also higher in the obstruction group than that in the control group [2.26 (1.31–3.42) vs. 1.06 (0.82–1.36); p = 0.0030] (Fig. 3).
      Fig. 2
      Fig. 2Comparison of peak diastolic blood flow velocity in the left main coronary artery (LM). (A) No significant differences were observed in the flow velocities before the transcatheter aortic valve replacement (TAVR) procedure between patients who developed left coronary artery (LCA) ostial obstruction and those who did not (controls). (B) The left main coronary artery blood flow velocity after TAVR was significantly higher in patients with LCA obstruction as compared with the controls. In the obstruction group, black and white circle marks show the velocity in the patients with stable and unstable hemodynamics, respectively.
      Fig. 3
      Fig. 3Comparison of pre- to post- transpercutaneous aortic valve replacement (TAVR) left main blood flow velocity ratio. The post- to pre-TAVR left main coronary artery (LM) blood flow velocity ratio was significantly higher in patients with left coronary (LCA) obstruction as compared with the controls. In the obstruction group, black and white circle marks show the ratio in the patients with stable and unstable hemodynamics, respectively.

      Detailed data of nine patients with LCA obstruction

      Detailed data for each patient who developed LCA obstruction are shown in Table 2. Three patients (#1, #5, and #9) developed severe hypotension and hemodynamic collapse, which required inotropic agents and/or mechanical support, such as intra-aortic balloon pumping or percutaneous cardiopulmonary support. These three patients were categorized as hemodynamically unstable LCA obstructions and the remaining six as stable LCA obstructions. The peak diastolic LM blood flow velocity was ≥0.90 m/s in five of six patients with stable LCA obstruction, whereas <0.90 m/s in all patients with unstable LCA obstruction. The post- to pre-TAVR flow velocity ratio was >2.0 in all patients with stable LM obstruction but <2.0 in all patients with unstable LCA obstruction. The LM flow velocity after coronary revascularization was recorded in patients #5, #6, #7, #8, and #9, all of whom underwent PCI. In patients #6, #7, and #8, the velocity after PCI decreased to the pre-TAVR levels. However, the velocity after PCI did not change significantly in patients #5 and #9 who belonged to the unstable LCA obstruction group. The diagnosis of LCA obstruction was made based on coronary angiography alone in all patients. In patient #8, an instantaneous wave-free ratio (iFR) in left anterior descending artery was 0.65 and improved to 0.97 after PCI (Fig. 4).
      Fig. 4
      Fig. 4The images of left main coronary artery (LM) blood flow velocity measurement, aortography, coronary angiography, and instantaneous wave-free ratio (iFR) measurement in a patient with a LM obstruction. Aortography after deploying transcatheter heart valve (THV) showed 50 % ostial LM stenosis (A). The LM peak blood flow velocity was 0.48 m/s before the transcatheter aortic valve replacement procedure (B) and increased to 1.00 m/s after THV deployment (C). Coronary angiography revealed significant LM ostial stenosis (D). A drug-eluting stent was deployed at ostial LM (E). The LM flow velocity was decreased to 0.45 m/s (F) after revascularization. The instantaneous iFR in left anterior descending artery was 0.65 after THV deployment and improved to 0.97 (G, H).

      Characteristics of “false positive” patients

      The characteristics of the patients who showed the flow velocity after transcatheter heart valve (THV) deployment of >0.90 m/s but did not have LCA ostial obstruction are summarized in Online Table 1. These 24 patients had higher mean pressure gradient, smaller aortic valve area, and aortic valve flow velocity measured by preprocedural transthoracic echocardiography (TTE) than the remaining 1072 patients in the control group [67 (49–86) vs. 50 (39–64) mm Hg; p < 0.001, 5.2 (4.7–5.9) vs. 4.6 (4.1–5.1) m/s; p = 0.022, 0.62 (0.56–0.73) vs. 0.73 (0.60–0.86) cm2; p < 0.001]. Aortic annular area, annular perimeter, and sinus of Valsalva diameter assessed by CT were significantly smaller in these false positive patients than those of the remaining.
      The characteristics of 49 patients who showed the flow velocity ratio of >2.0 but did not have LCA ostial obstruction are shown in Online Table 2. The 12 (20.3 %) patients were included in the first 50 patients of the LM flow velocity measurement (p < 0.001). Transapical approach was associated with the higher incidence of false positive (6.7 % vs. 1.9 %, p = 0.036).

      Discussion

      The major finding of the current study is that the peak diastolic blood flow velocity in the LM after TAVR and the pre- to post-TAVR flow velocity ratio were higher in patients who developed LCA ostial obstruction as compared with those who did not. Furthermore, these parameters were lower in patients with hemodynamically unstable LCA obstruction than those with stable LCA obstruction. This result suggests that the measurement of coronary blood flow velocity in the LM would be useful to detect stable LCA obstruction in patients undergoing TAVR.

      Increased LM blood flow velocity in LCA stenosis

      Studies, in which coronary blood flow velocity in the LM was measured by TEE in patients with LM coronary artery stenosis, demonstrated that the peak diastolic LM blood flow velocities in the stenotic segment were higher than in the non-stenotic segment [
      • Yasu T.
      • Yamagishi M.
      • Beppu S.
      • Nagata S.
      • Miyatake K.
      Left main coronary flow velocity associated with stenosis. Evaluation by transesophageal color-guided pulsed doppler technique.
      ,
      • Yamagishi M.
      • Yasu T.
      • Ohara K.
      • Kuro M.
      • Miyatake K.
      Detection of coronary blood flow associated with left main coronary artery stenosis by transesophageal doppler color flow echocardiography.
      ]. Laminar peak flow velocity in a normal coronary artery has been reported as 0.21 ± 0.08 to 0.28 ± 0.09 m/s [
      • Youn H.J.
      • Jeon H.K.
      • Cho E.J.
      • Oh Y.S.
      • Chung W.S.
      • Kim J.H.
      • et al.
      Slow flow on distal left anterior descending coronary artery demonstrated by transthoracic doppler echocardiography predicts pathologic flow dynamics.
      ,
      • Hozumi T.
      • Yoshida K.
      • Ogata Y.
      • Akasaka T.
      • Asami Y.
      • Takagi T.
      • et al.
      Noninvasive assessment of significant left anterior descending coronary artery stenosis by coronary flow velocity reserve with transthoracic color doppler echocardiography.
      ,
      • Pizzuto F.
      • Voci P.
      • Mariano E.
      • Puddu P.E.
      • Spedicato P.
      • Romeo F.
      Coronary flow reserve of the angiographically normal left anterior descending coronary artery in patients with remote coronary artery disease.
      ]. The TEE-based peak flow velocity of ≥1.5 m/s was reported to show 85 % sensitivity and 88 % specificity to detect left main coronary artery disease [
      • Anjaneyulu A.
      • Raghu K.
      • Chandramukhi S.
      • Satyajit G.M.
      • Arramraja S.
      • Raghavaraju P.
      • et al.
      Evaluation of left main coronary artery stenosis by transthoracic echocardiography.
      ]. A criterion of twice the peak flow velocity compared to a non-stenotic site, or the local flow velocity of 2.0 m/s, showed 96–100 % specificity to diagnose coronary artery stenosis site [
      • Krzanowski M.
      • Bodzoń W.
      • Brzostek T.
      • Nizankowski R.
      • Szczeklik A.
      Value of transthoracic echocardiography for the detection of high-grade coronary artery stenosis: prospective evaluation in 50 consecutive patients scheduled for coronary angiography.
      ]. Hozumi et al. [
      • Hozumi T.
      • Yoshida K.
      • Akasaka T.
      • Asami Y.
      • Kanzaki Y.
      • Ueda Y.
      • et al.
      Value of acceleration flow and the prestenotic to stenotic coronary flow velocity ratio by transthoracic color doppler echocardiography in noninvasive diagnosis of restenosis after percutaneous transluminal coronary angioplasty.
      ] reported that the cut-off value of the prestenotic-to-stenotic mean diastolic velocity ratio of <0.45 showed 86 % sensitivity and 93 % specificity for restenosis in the left anterior descending artery lesions [
      • Hozumi T.
      • Yoshida K.
      • Akasaka T.
      • Asami Y.
      • Kanzaki Y.
      • Ueda Y.
      • et al.
      Value of acceleration flow and the prestenotic to stenotic coronary flow velocity ratio by transthoracic color doppler echocardiography in noninvasive diagnosis of restenosis after percutaneous transluminal coronary angioplasty.
      ]. Similarly, Saraste et al. [
      • Saraste M.
      • Vesalainen R.K.
      • Ylitalo A.
      • Saraste A.
      • Koskenvuo J.W.
      • Toikka J.O.
      • et al.
      Transthoracic doppler echocardiography as a noninvasive tool to assess coronary artery stenoses - a comparison with quantitative coronary angiography.
      ] reported pre-stenotic-to-stenotic peak flow velocity ratio of >2.0 resulted in 82 % sensitivity and 92 % specificity in the detection of stenosis in three main branches. As above, coronary blood flow velocity in the LM by TEE measurement is useful to detect stenotic lesions in the LCA. In the current study, coronary blood flow was accelerated in the LCA obstruction site post-TAVI, similar to previous studies on coronary artery stenosis. Therefore, we believe our hypothesis was substantiated from this study and was also supported by the fact that the accelerated blood flow velocity was decreased after a successful PCI in patients #6–#8.

      Diagnostic accuracy of aortography and coronary angiography

      When clear findings including severe hypotension, abnormal left ventricular wall motion in echocardiography, and ST-T change in electrocardiogram are shown, it is easy to diagnose LCA ostial obstruction. However, some patients do not demonstrate any clinical findings. Moreover, LCA obstruction is sometimes very difficult to be diagnosed by angiography because the complication is not caused only by stenosis but also by the valve prosthesis itself, the native leaflets, calcifications, or dissection [
      • Kappetein A.P.
      • Head S.J.
      • Généreux P.
      • Piazza N.
      • van Mieghem N.M.
      • Blackstone E.H.
      • et al.
      Updated standardized endpoint definitions for transcatheter aortic valve implantation: the valve academic research Consortium-2 consensus document (VARC-2).
      ]. The “delayed” coronary obstruction [
      • Higuchi R.
      • Mahara K.
      • Naito K.
      • Takamisawa I.
      • Shimizu J.
      • Iguchi N.
      • et al.
      Silent coronary obstruction following transcatheter aortic valve implantation: detection by transesophageal echocardiography.
      ,
      • Jabbour R.J.
      • Tanaka A.
      • Finkelstein A.
      • Mack M.
      • Tamburino C.
      • Van Mieghem N.
      • et al.
      Delayed coronary obstruction after transcatheter aortic valve replacement.
      ] patients in previous studies might be “missed” patients in the TAVR procedures.

      Detection of “silent” LCA ostial obstruction

      Coronary blood flow strongly depends on many hemodynamic factors, such as coronary perfusion pressure, heart rate, coronary vascular resistance, and myocardial mass [
      • Hozumi T.
      • Yoshida K.
      • Ogata Y.
      • Akasaka T.
      • Asami Y.
      • Takagi T.
      • et al.
      Noninvasive assessment of significant left anterior descending coronary artery stenosis by coronary flow velocity reserve with transthoracic color doppler echocardiography.
      ,
      • Pizzuto F.
      • Voci P.
      • Mariano E.
      • Puddu P.E.
      • Spedicato P.
      • Romeo F.
      Coronary flow reserve of the angiographically normal left anterior descending coronary artery in patients with remote coronary artery disease.
      ,
      • Rouleau J.
      • Boerboom L.E.
      • Surjadhana A.
      • Hoffman J.I.
      The role of autoregulation and tissue diastolic pressures in the transmural distribution of left ventricular blood flow in anesthetized dogs.
      ,
      • Feigl E.O.
      Coronary physiology.
      ]. Severely decreased aortic and coronary perfusion pressure in patients with LCA ostial obstruction reduces coronary blood flow and flow velocity; thus, increased coronary blood flow velocities were not observed in hemodynamically unstable patients. In this study, accelerated LM blood flow by TEE was not observed in all the three patients who developed unstable LCA obstruction. Thus, the intraprocedural TEE measurement of the LM flow velocities would be useful to detect stable LCA ostial obstruction but not unstable LCA ostial obstruction. Asymptomatic LCA occlusion may not be diagnosed during the TAVR treatment; however, it is diagnosed in the delayed phase, that is, as delayed coronary artery occlusion [
      • Higuchi R.
      • Mahara K.
      • Naito K.
      • Takamisawa I.
      • Shimizu J.
      • Iguchi N.
      • et al.
      Silent coronary obstruction following transcatheter aortic valve implantation: detection by transesophageal echocardiography.
      ,
      • Jabbour R.J.
      • Tanaka A.
      • Finkelstein A.
      • Mack M.
      • Tamburino C.
      • Van Mieghem N.
      • et al.
      Delayed coronary obstruction after transcatheter aortic valve replacement.
      ]. In this study, patient #8 did not show any clinical, electrocardiographic, or echocardiographic findings, except for increased TEE-based LM blood flow velocity and severely decreased iFR and fractional flow reserve. We believe that the detection of asymptomatic LCA obstruction would be promising to prevent delayed coronary obstruction [
      • Jabbour R.J.
      • Tanaka A.
      • Finkelstein A.
      • Mack M.
      • Tamburino C.
      • Van Mieghem N.
      • et al.
      Delayed coronary obstruction after transcatheter aortic valve replacement.
      ,
      • Klocke F.J.
      Coronary blood flow in man.
      ,
      • Duncker D.J.
      • Bache R.J.
      Regulation of coronary blood flow during exercise.
      ,
      • Bagur R.
      • Dumont E.
      • Doyle D.
      • Larose E.
      • Lemieux J.
      • Bergeron S.
      • et al.
      Coronary ostia stenosis after transcatheter aortic valve implantation.
      ,
      • Spiro J.
      • Nadeem A.
      • Doshi S.N.
      Delayed left main stem obstruction following successful TAVI with an Edwards SAPIEN XT valve: successful resuscitation and percutaneous coronary intervention using a non-invasive automated chest compression device (AutoPulse).
      ,
      • Jategaonkar S.R.
      • Dimitriadis Z.
      • Hakim-Meibodi K.
      • Gummert J.
      • Horstkotte D.
      • Scholtz W.
      Delayed coronary ischemia after transfemoral aortic valve implantation.
      ,
      • Isawa T.
      • Tada N.
      • Ootomo T.
      Delayed-onset left main coronary artery obstruction more than 24 hours after balloon-expandable transcatheter aortic valve replacement.
      ].

      The cut-off value for LCA obstruction

      Determining a specific cut-off value of the TEE-based LM flow velocity to detect LCA obstruction is difficult because the coronary blood flow velocity is affected by various hemodynamic factors and technical issues, including the depth of scanning, quality of pulse-wave Doppler pattern, scan angle, or LM flow direction. The LM blood flow velocity measured by TEE in patients with LM coronary artery stenosis was reported to be 0.90 ± 0.32 to 1.16 ± 0.28 m/s at the stenotic segment [
      • Yasu T.
      • Yamagishi M.
      • Beppu S.
      • Nagata S.
      • Miyatake K.
      Left main coronary flow velocity associated with stenosis. Evaluation by transesophageal color-guided pulsed doppler technique.
      ,
      • Yamagishi M.
      • Yasu T.
      • Ohara K.
      • Kuro M.
      • Miyatake K.
      Detection of coronary blood flow associated with left main coronary artery stenosis by transesophageal doppler color flow echocardiography.
      ]. When a cut-off value of the LM blood flow velocity was 0.90 m/s in this study, the flow velocity was ≥0.90 m/s in five of six patients with the stable LCA obstruction, whereas <0.90 m/s in all patients with unstable LCA obstruction because of hemodynamic collapse. Although these values may be used as references, coronary flow velocities measured by TTE or TEE increase even in patients without any stenotic lesion [
      • Anjaneyulu A.
      • Raghu K.
      • Chandramukhi S.
      • Satyajit G.M.
      • Arramraja S.
      • Raghavaraju P.
      • et al.
      Evaluation of left main coronary artery stenosis by transthoracic echocardiography.
      ,
      • Krzanowski M.
      • Bodzoń W.
      • Brzostek T.
      • Nizankowski R.
      • Szczeklik A.
      Value of transthoracic echocardiography for the detection of high-grade coronary artery stenosis: prospective evaluation in 50 consecutive patients scheduled for coronary angiography.
      ,
      • Hozumi T.
      • Yoshida K.
      • Akasaka T.
      • Asami Y.
      • Kanzaki Y.
      • Ueda Y.
      • et al.
      Value of acceleration flow and the prestenotic to stenotic coronary flow velocity ratio by transthoracic color doppler echocardiography in noninvasive diagnosis of restenosis after percutaneous transluminal coronary angioplasty.
      ,
      • Saraste M.
      • Vesalainen R.K.
      • Ylitalo A.
      • Saraste A.
      • Koskenvuo J.W.
      • Toikka J.O.
      • et al.
      Transthoracic doppler echocardiography as a noninvasive tool to assess coronary artery stenoses - a comparison with quantitative coronary angiography.
      ,
      • Yasu T.
      • Yamagishi M.
      • Beppu S.
      • Nagata S.
      • Miyatake K.
      Left main coronary flow velocity associated with stenosis. Evaluation by transesophageal color-guided pulsed doppler technique.
      ,
      • Yamagishi M.
      • Yasu T.
      • Ohara K.
      • Kuro M.
      • Miyatake K.
      Detection of coronary blood flow associated with left main coronary artery stenosis by transesophageal doppler color flow echocardiography.
      ], as also shown in the present study cohort. Conversely, the post- to pre-TAVR peak blood flow velocity ratio may be more reliable, because it is less affected by personal anatomical factors and technical issues. Previous studies demonstrated that the blood flow velocity ratio at the stenotic segment to the non-stenotic segment of 2.0 can be used as a cut-off value [
      • Hozumi T.
      • Yoshida K.
      • Akasaka T.
      • Asami Y.
      • Kanzaki Y.
      • Ueda Y.
      • et al.
      Value of acceleration flow and the prestenotic to stenotic coronary flow velocity ratio by transthoracic color doppler echocardiography in noninvasive diagnosis of restenosis after percutaneous transluminal coronary angioplasty.
      ,
      • Saraste M.
      • Vesalainen R.K.
      • Ylitalo A.
      • Saraste A.
      • Koskenvuo J.W.
      • Toikka J.O.
      • et al.
      Transthoracic doppler echocardiography as a noninvasive tool to assess coronary artery stenoses - a comparison with quantitative coronary angiography.
      ]. We speculate that the 2.0 as a cut-off value of stenotic to non-stenotic flow velocity ratio to detect a significant stenotic lesion would be applied to post- to pre-TAVR peak blood flow velocity ratio for the detection of stable LCA obstruction. In the current study, all six patients who developed stable LCA obstruction showed post- to pre-TAVR peak blood flow velocity ratio of >2.0 although all of the remaining three patients with unstable LCA showed the ratio of <2.0 because of hemodynamic collapse. This finding suggests that the cut-off determines LM obstruction without false negative which means 100 % sensitivity, under the condition of hemodynamic stability. However, the ratio of 2.0 is still far from the established cut-off value to diagnose LCA obstruction because of insufficient statistical power. Approaches using multimodality would be important to avoid missing silent LCA ostial obstruction during a procedure.

      Causes of “false positive”

      There is a trade-off relationship between sensitivity and specificity that is dependent on the cut-off level. Therefore, non-negligible numbers of false positive were found in the study when using the cut-off levels. As shown in Online Tables 1 and 2, the results suggested a smaller aortic valve and a higher severity of aortic stenosis were associated with higher coronary flow velocity, even after THV deployment. Furthermore, some experience may be required to measure the flow velocity ratio accurately, because our first 50 patients included 12 false positive patients. A left ventricular incision may also affect cardiac output and coronary artery flow velocity. In addition, changes in hemodynamic factors after a TAVR procedure, such as coronary perfusion pressure or heart rate might affect the present outcomes [
      • Rouleau J.
      • Boerboom L.E.
      • Surjadhana A.
      • Hoffman J.I.
      The role of autoregulation and tissue diastolic pressures in the transmural distribution of left ventricular blood flow in anesthetized dogs.
      ,
      • Feigl E.O.
      Coronary physiology.
      ,
      • Klocke F.J.
      Coronary blood flow in man.
      ,
      • Duncker D.J.
      • Bache R.J.
      Regulation of coronary blood flow during exercise.
      ].

      Can TTE measure the LM flow?

      If peak blood flow velocity in the LM could be measured by TTE as well as TEE, it can be helpful in patients undergoing TAVR under local anesthesia and conscious sedation. Vegsundvåg et al. [
      • Vegsundvåg J.
      • Holte E.
      • Wiseth R.
      • Hegbom K.
      • Hole T.
      Transthoracic echocardiography for imaging of the different coronary artery segments: a feasibility study.
      ] reported that TTE imaging of the LM including flow velocity measurement succeeded in 98 % of patients. Hozumi et al. also achieved >90 % feasibility of coronary flow imaging [
      • Hozumi T.
      • Yoshida K.
      • Ogata Y.
      • Akasaka T.
      • Asami Y.
      • Takagi T.
      • et al.
      Noninvasive assessment of significant left anterior descending coronary artery stenosis by coronary flow velocity reserve with transthoracic color doppler echocardiography.
      ]. Other groups reported that technology of coronary flow imaging by TTE improved with experience [
      • Pizzuto F.
      • Voci P.
      • Mariano E.
      • Puddu P.E.
      • Spedicato P.
      • Romeo F.
      Coronary flow reserve of the angiographically normal left anterior descending coronary artery in patients with remote coronary artery disease.
      ,
      • Voci P.
      • Testa G.
      • Plaustro G.
      Imaging of the distal left anterior descending coronary artery by transthoracic color-doppler echocardiography.
      ,
      • Dimitrow P.P.
      • Krzanowski M.
      • Niżankowski R.
      • Szczeklik A.
      • Dubiel J.S.
      Effect of verapamil on systolic and diastolic coronary blood flow velocity in asymptomatic and mildly symptomatic patients with hypertrophic cardiomyopathy.
      ,
      • Dimitrow P.P.
      • Krzanowski M.
      • Niżankowski R.
      • Szczeklik A.
      • Dubiel J.S.
      Verapamil improves the response of coronary vasomotion to cold pressor test in asymptomatic and mildly symptomatic patients with hypertrophic cardiomyopathy.
      ,
      • Dimitrow P.P.
      • Krzanowski M.
      • Niżankowski R.
      • Szczeklik A.
      • Dubiel J.S.
      Comparison of the effect of verapamil and propranolol on response of coronary vasomotion to cold pressor test in symptomatic patients with hypertrophic cardiomyopathy.
      ]. These findings suggested TTE can be used to detect LCA obstruction. Nevertheless, further research is needed to establish the feasibility in the TAVR population, because it probably depends on the skill levels of the examiner or patient population characteristics. At present, it may be pragmatic to conduct TAVI under general anesthesia and to assess TEE-based LM flow velocity only for patients highly at risk of coronary obstruction.

      Limitations

      First, this is a single-center and retrospective study. Second, some problems of statistical reliability were encountered due to the small number of LCA ostial obstruction cases in the cohort.

      Conclusion

      Coronary blood flow velocity in the LM significantly increased in patients with LCA obstruction without hemodynamic collapse. Thus, the intraprocedural TEE measurement of coronary blood flow velocities was useful as a diagnostic tool for silent LCA ostial obstruction.

      Funding

      This research received no grant from any funding agency in the public, commercial, or not-for-profit sectors.

      Declaration of competing interest

      Norio Tada, Yusuke Enta, Masaki Miyasaka, and Masaki Nakashima received lecture fees from Edwards Lifescience. The other authors have no conflict of interest.

      Acknowledgments

      We are grateful to Crimson Interactive Japan Co., Ltd. (https://www.enago.jp) for carefully proofreading the manuscript. The scientific meeting at which the data have already been presented.

      Appendix A. Supplementary data

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