# Changes in microcirculation following transcatheter aortic valve implantation in patients with stable coronary artery disease

Quentin Battistolo, Robin Le Ruz, Pierre-Guillaume Piriou, Patrice Guerin, Vincent Letocart, Julien Plessis, Alexandra Poinas, Thomas Senage, Thibaut Manigold

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Quentin Battistolo, Robin Le Ruz, Pierre-Guillaume Piriou, Patrice Guerin, Vincent Letocart, et al. Changes in microcirculation following transcatheter aortic valve implantation in patients with stable coronary artery disease. Archives of cardiovascular diseases, 2024, 118 (4), pp.222 - 230. 10.1016/j.acvd.2024.12.006. hal-05241338

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Clinical Research

# Changes in microcirculation following transcatheter aortic valve implantation in patients with stable coronary artery disease

Quentin Battistolo<sup>a,*</sup>, Robin Le Ruz<sup>a</sup>, Pierre-Guillaume Piriou<sup>a</sup>, Patrice Guerin<sup>a</sup>, Vincent Letocart<sup>a</sup>, Julien Plessis<sup>a</sup>, Alexandra Poinas<sup>b</sup>, Thomas Senage<sup>c</sup>, Thibaut Manigold<sup>a</sup>

<figure><img src="image_3.png" /></figure>

ARTICLE INFO

Article history:

Received 15 August 2024

Received in revised form

21 November 2024

Accepted 2 December 2024

Available online 21 December 2024

Keywords:

Aortic stenosis

Coronary artery disease

Coronary flow reserve

Fractional flow reserve

Transcatheter aortic valve implantation

ABSTRACT

**Background:** Few studies have assessed coronary physiology in the setting of coronary artery disease (CAD) with severe aortic stenosis (AS). Fractional flow reserve (FFR) to guide revascularization in such patients is not validated.

**Aims:** We describe changes in coronary physiology in this population before and after transcatheter aortic valve implantation (TAVI).

**Methods:** Patients with stable CAD and severe AS treated with TAVI were prospectively included during 2020–2023. Coronary physiology was assessed before and immediately after TAVI, and at follow-up (median 5.4 months).

**Results:** Twenty-nine patients (mean age 81.3 years) were included. Median (95% confidence interval) FFR decreased numerically, from 0.83 (0.79–0.84) pre-TAVI to 0.81 (0.78–0.83) post-TAVI. During hyperaemia, the transit mean time reduced numerically, from 0.27 (0.19–0.35) to 0.20 (0.18–0.27) seconds, reflecting increased coronary flow. Basal microvascular resistance increased numerically, from 24 (21–35) to 32 (23–45), while resistive reserve ratio increased significantly, from 1.8 (1.5–2.3) to 2.6 (2.2–3.1) (P = 0.002). Consequently, coronary flow reserve (CFR) improved significantly, from 1.5 (1.2–1.7) to 1.9 (1.5–2.4) (P = 0.006). Among 21 patients with follow-up, no significant change in FFR was observed and the significance of the increase in CFR was lost. Only three patients had an index of microvascular resistance > 25, indicating microvascular impairment during hyperaemia.

**Conclusions:** In stable CAD patients treated with TAVI for severe AS, valve replacement provides an immediate improvement in CFR. FFR shows a minimal decrease after valve implantation, supporting its reproducibility to guide revascularization in such patients.

**Clinical trial registration:** NCT04663334.

© 2024 The Author(s). Published by Elsevier Masson SAS. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

1. Abbreviations

AS aortic stenosis

CAD coronary artery disease

CFR coronary flow reserve

CI confidence interval

FFR fractional flow reserve

IMR index of microvascular resistance

IQR interquartile range

LAD left anterior descending

LVEF left ventricular ejection fraction

NOTION-3 Third Nordic Aortic Valve Intervention

Pa aortic pressure

Pd distal pressure

RRR resistive reserve ratio

TAVI transcatheter aortic valve implantation

Tnm transit mean time

<footnote><sup>a</sup> Nantes Université, CHU Nantes, Unité Hémodynamique et Cardiologie Interventionnelle, l'institut du thorax, 44000 Nantes, France</footnote>

<footnote><sup>b</sup> Nantes Université, CHU Nantes, INSERM, Département Investigation et Recherche Translationnelle - CIC 1413, l'institut du thorax, 44000 Nantes, France</footnote>

<footnote><sup>c</sup> Nantes Université, CHU Nantes, Service de chirurgie thoracique et cardiovasculaire, Unité de transplantation thoracique, l'institut du thorax, 44000 Nantes, France</footnote>

<footnote>* Corresponding author. Institut du Thorax - Unité Hémodynamique et Cardiovasculaire Interventionnelle, boulevard Jacques-Monod, Saint-Herblain, 44093 Nantes cedex, France.</footnote>

<footnote>E-mail address: quentin.battistolo@hotmail.fr (Q. Battistolo).</footnote>
## 2. Introduction

Transcatheter aortic valve implantation (TAVI) is the first-line treatment of severe aortic stenosis (AS) in older adults at high surgical risk or who are ineligible for surgery [1-3]. Since its inception, it has significantly reduced the occurrence of peri-operative complications [4]. TAVI indications are now being expanded to include younger patients with low surgical risk [5-7].

Many pathophysiological factors are common between degenerative AS and atherosclerosis [8,9]. The presence of significant coronary artery disease (CAD) in patients undergoing TAVI is frequent, with a prevalence of up to 60% for patients with intermediate or high surgical risk and 30% for patients with low risk [10,11], and these patients have a higher co-morbidity burden than those in a surgical population [12]. The prognostic impact of significant CAD in patients treated with TAVI is unclear, and conflicting results have been reported [13,14]. At 2 years, the rate of coronary events following TAVI is estimated to be 10%, and the occurrence of acute coronary syndrome following TAVI has been associated with a poor prognosis [15,16].

Few studies have assessed the coronary physiology of CAD patients in the context of AS treated with TAVI. Currently, invasive assessment of fractional flow reserve (FFR) is recommended to guide revascularization in stable CAD patients with intermediate to significant coronary stenosis or multitruncular disease [17] and a positivity threshold ≤ 0.8 is recommended to proceed with revascularization. However, FFR is not currently validated for guiding revascularization in patients with CAD and severe AS.

AS alters left ventricular filling pressures by obstructing ejection and this, in turn, causes myocardial remodelling through compensatory hypertrophy [18-20]. This remodelling is accompanied by cellular and interstitial damage in the myocardium, which may cause a change in coronary reserve. This is thought to alter adenosine-induced hyperaemia and the functional evaluation of coronary stenosis. Whether rapid reverse myocardial remodelling after aortic valve replacement [21,22] restores coronary flow reserve (CFR) is unknown and the effect on FFR has only been investigated in a few recent observational studies [23-26].

The purpose of this study was to describe immediate and remote changes in coronary physiology indices, including CFR and resistive reserve ratio (RRR), as well as changes in FFR, in patients with stable CAD undergoing TAVI for severe AS.

## 3. Methods

### 3.1. Population

Between 2020 and 2023, we conducted a single-centre, prospective, observational study in Nantes University Hospital. Study participants were men and women over the age of 18 years, with known symptomatic severe AS treated with TAVI and stable preoperative CAD (epicardial stenosis between 50% and 90%), whether symptomatic or not. Exclusion criteria included acute coronary syndrome, severe multitruncular stenosis or critical lesions (> 90%) of the left main or proximal left anterior descending (LAD) artery, non-viable infarct sequelae in the territory related to the studied artery, history of coronary artery bypass surgery, severe impairment of left ventricular ejection fraction (LVEF < 35%), severe renal failure (estimated glomerular filtration rate < 30 mL/min/1.73 m²), and contraindication to intravenous adenosine.

The decision to treat patients with significant CAD with coronary angioplasty, optimal medical treatment alone, or physiological assessment by FFR, including measurement before and after TAVI, was taken by the local Heart Team. Invasive procedures were performed as part of the patient care pathway for the management of symptomatic severe AS.

### 3.2. Invasive assessments

Coronary angiography was performed via the femoral access (14 or 16 French sheath depending on the valve) during TAVI, and via radial or femoral access (6 French sheath), at the operator's discretion, during the follow-up procedure. During the procedure, all patients received a weight-adjusted dose of unfractionated heparin (50 IU/kg). Aortic pressure calibration (zeroing) was done at the heart level. Angiography of the target vessel was performed with at least two orthogonal views following administration of a standard dose of 1 mg isosorbide dinitrate.

Invasive assessment of target coronary lesions was performed with the PressureWire X Guidewire (Abbott Vascular, Chicago, Illinois, United States), outfitted with pressure and temperature sensors to obtain physiological indices by the intracoronary thermodilution method [27]. The guidewire was rinsed with saline outside the patient before being calibrated to the aortic pressure (Pa) by placing the pressure sensor at the guidewire outlet. After pressure equalization, it was positioned 1 cm downstream from the target lesion. Angiography was used to document the position of the guidewire, allowing for identical repositioning on subsequent measurements.

The measurements were taken in the basal state and at least 1 min 30 s after initiation of a continuous infusion of intravenous adenosine at a dose of 140 mg/kg/min to achieve maximum coronary hyperaemia. For thermodilution indices, boluses of 3 mL room-temperature saline were intracoronary delivered until three reproducible values of transit mean time (Tnm), at rest and during hyperaemia, could be obtained. When the guidewire was removed, the equalization of aortic and guidewire pressures was checked to ensure there was no drift.

Data collected by the guidewire was wirelessly transmitted to a computer and analysed using CoroFlow Coroventis software (Abbott Vascular, Chicago, Illinois, United States). For each target lesion, the following thermodilution indices were collected: Pa, distal pressure (Pd), FFR, Tnm, CFR (= basal Tnm/hyperaemic Tnm), index of microvascular resistance (IMR = hyperaemic Tnm × hyperaemic Pd), RRR (= basal microvascular resistance/IMR) and basal microvascular resistance (= basal Tnm × basal Pd or = RRR × IMR).

The coronary physiology evaluation was performed during the TAVI procedure before and immediately after valve deployment and it was repeated 3-6 months later. The operator chose both the coronary angioplasty indication and the timing of the procedure.

### 3.3. Statistical analysis

Continuous variables are shown as mean ± standard deviation (minimum-maximum), median (interquartile range [IQR]) or median (95% confidence interval [CI]), and categorical variables as number and percentage. For each target lesion, the Friedman test was used to compare variables before and after TAVI. To control the inflation of the alpha risk due to multiplicity of test, the Benjamini-Hochberg method was used. MedCalc® Statistical Software version 22.014 (MedCalc Software Ltd, Ostend, Belgium) was used for all analyses.

### 3.4. Ethical considerations

The NCT04663334 study was conducted in accordance with the relevant versions of the French Public Health Code, national and international Good Clinical Practice guidelines, and the Declaration of Helsinki. After the investigator had provided the information about the study as outlined in the information and consent form, patients confirmed orally that they had no objection to participate in the trial, as mandated by French law for this type of study. This
<table><caption>**Table 1**
Baseline characteristics prior to TAVI.</caption><thead><tr><th></th><th>Patients (n = 29)</th></tr></thead><tbody><tr><td>Age (years)</td><td>81.3 ± 3.5 (74–87)</td></tr><tr><td>Male sex</td><td>21 (72.4%)</td></tr><tr><td>Body mass index (kg/m²)</td><td>28.9 ± 5.1 (18.3–46.5)</td></tr><tr><td>Smoker</td><td>13 (44.8)</td></tr><tr><td>Diabetes</td><td>6 (20.7)</td></tr><tr><td>Hypertension</td><td>28 (96.6)</td></tr><tr><td>Dyslipidaemia</td><td>25 (86.2)</td></tr><tr><td>Previous myocardial infarction<sup>a</sup></td><td>8 (27.6)</td></tr><tr><td>Atrial fibrillation/ flutter</td><td>5 (17.2)</td></tr><tr><td>Extracardiac arterial disease</td><td>2 (6.9)</td></tr><tr><td>History of stroke</td><td>2 (6.9)</td></tr><tr><td>Pacemaker</td><td>2 (6.9)</td></tr><tr><td>Treatments</td><td></td></tr><tr><td>Beta-blocker</td><td>14 (48.3)</td></tr><tr><td>Calcium blockers</td><td>11 (37.9)</td></tr><tr><td>RAAS blockers</td><td>17 (58.6)</td></tr><tr><td>Antiplatelet therapy</td><td>20 (69.0)</td></tr><tr><td>Anticoagulants</td><td>6 (20.7)</td></tr><tr><td>Statins</td><td>19 (65.5)</td></tr><tr><td>Estimated glomerular filtration rate</td><td></td></tr><tr><td>≥ 90 mL/min/1.73 m²</td><td>2 (6.9)</td></tr><tr><td>60–89 mL/min/1.73 m²</td><td>21 (72.4)</td></tr><tr><td>45–59 mL/min/1.73 m²</td><td>3 (10.3)</td></tr><tr><td>30–44 mL/min/1.73 m²</td><td>3 (10.3)</td></tr><tr><td>EuroSCORE II</td><td>2.9 ± 2.2 (1.0–9.4)</td></tr><tr><td>STS score</td><td>3.9 ± 2.5 (1.4–12.1)</td></tr><tr><td>LVEF > 50%</td><td>27 (93.1)</td></tr><tr><td>LVEF 40–49%</td><td>2 (6.9)</td></tr><tr><td>Aortic valve area (cm²)</td><td>0.74 ± 0.18 (0.37–1.03)</td></tr><tr><td>Transvalvular aortic Vmax (m/s)</td><td>4.6 ± 0.5 (3.4–5.7)</td></tr><tr><td>Mean gradient (mmHg)</td><td>56 ± 13 (30–89)</td></tr><tr><td>Implanted prosthesis</td><td></td></tr><tr><td>Edwards Sapien</td><td>27 (93.1)</td></tr><tr><td>20 mm</td><td>1 (3.4)</td></tr><tr><td>23 mm</td><td>7 (24.1)</td></tr><tr><td>26 mm</td><td>13 (44.8)</td></tr><tr><td>29 mm</td><td>6 (20.7)</td></tr><tr><td>Corevalve 30 mm</td><td>1 (3.4)</td></tr><tr><td>Acurate S</td><td>1 (3.4)</td></tr></tbody></table>

Data are expressed as number (%) or mean ± standard deviation (minimum–maximum). LVEF: left ventricular ejection fraction; RAAS: renin–angiotensin-aldosterone system; STS: Society of Thoracic Surgeons; TAVI: transcatheter aortic valve implantation; Vmax: maximum velocity.

a > 12 months before enrolment.

study was approved by the local Ethics Committee (Groupe Nantais d'Ethique dans le Domaine de la Santé).

## 4. Results

Twenty-nine patients were included in the study between December 2020 and February 2023. The mean patient age was 81.3 ± 3.5 years (Table 1). Most patients had hypertension (96.6%), 20.7% had diabetes and 27.6% had a history of myocardial infarction. LVEF was > 50% in 93.1% of patients. The mean aortic valve area was 0.74 ± 0.18 cm² and the mean transaortic gradient was 56 ± 13 mmHg. Most patients (93.1%) were implanted with an Edwards Sapien valve.

Coronary physiology identified 29 angiographically intermediate to significant lesions (stenosis 50–70%) corresponding to one lesion per patient (Table 2). The LAD artery was involved in most lesions, with 18 lesions (58.0%) in the middle LAD and six (22.5%) in the proximal LAD. The remaining five lesions involved the right coronary artery. The mean degree of stenosis was 55.9% ± 9.9, the mean length was 7.9 ± 7.2 mm, and the mean minimum diameter was 1.45 ± 0.31 mm, according to quantitative coronary angiography. Operators visually classified 17 lesions (58.6%) as angiographically significant (stenosis ≥ 50%) and the remaining 12 lesions (41.4%) as intermediate (stenosis = 50%).

<table><caption>**Table 2**
Coronary artery disease characteristics.</caption><thead><tr><th>Variables</th><th>Patients (n = 29)</th></tr></thead><tbody><tr><td>Target vessel (stenosis ≥ 50%)</td><td></td></tr><tr><td>Middle LAD artery</td><td>18 (62.1)</td></tr><tr><td>Proximal LAD artery</td><td>6 (20.7)</td></tr><tr><td>Middle RCA</td><td>4 (13.8)</td></tr><tr><td>Proximal RCA</td><td>1 (3.4)</td></tr><tr><td>Quantitative coronary angiography</td><td></td></tr><tr><td>Degree of stenosis (%)</td><td>56 ± 10 (39–80)</td></tr><tr><td>Length of stenosis (mm)</td><td>7.9 ± 7.2 (9.7–37.7)</td></tr><tr><td>Minimum diameter (mm)</td><td>1.4 ± 0.3 (0.9–2.2)</td></tr><tr><td>Operator estimation of lesion significance</td><td></td></tr><tr><td>50%</td><td>12 (41.4)</td></tr><tr><td>50–70%</td><td>17 (58.6)</td></tr></tbody></table>

Data are expressed as number (%) or mean ± standard deviation (minimum–maximum). LAD: left anterior descending; RCA: right coronary artery.

<table><caption>**Table 3**
Haemodynamics after valve implantation.</caption><thead><tr><th rowspan="2"></th><th colspan="2">Study patients (n = 29)</th><th rowspan="2">P<sup>a</sup></th></tr><tr><th>Pre-TAVI</th><th>Post-TAVI</th></tr></thead><tbody><tr><td>Basal Pd (mmHg)</td><td>72 [57–77]</td><td>75 [64–87]</td><td>0.057</td></tr><tr><td>Basal Pa (mmHg)</td><td>81 [65–85]</td><td>82 [71–98]</td><td>0.057</td></tr><tr><td>Pd/Pa</td><td>0.89 [0.87–0.92]</td><td>0.89 [0.88–0.91]</td><td>0.18</td></tr><tr><td>Pd hyperaemia (mmHg)</td><td>54 [43–69]</td><td>57 [47–65]</td><td>0.33</td></tr><tr><td>Pa hyperaemia (mmHg)</td><td>66 [52–81]</td><td>75 [57–81]</td><td>0.083</td></tr><tr><td>FFR</td><td>0.83 (0.79–0.84)</td><td>0.81 (0.78–0.83)</td><td>0.039<sup>a</sup></td></tr><tr><td>Tnm basal (s)</td><td>0.34 [0.29–0.51]</td><td>0.38 [0.30–0.75]</td><td>0.71</td></tr><tr><td>Tnm hyperaemia (s)</td><td>0.27 (0.19–0.35)</td><td>0.20 (0.18–0.27)</td><td>0.039<sup>a</sup></td></tr><tr><td>Basal microvascular resistance</td><td>24 (21–35)</td><td>32 (23–45)</td><td>0.048<sup>a</sup></td></tr><tr><td>IMR</td><td>14 [10–19]</td><td>11 [9–18]</td><td>0.25</td></tr><tr><td>CFR</td><td>1.5 (1.2–1.7)</td><td>1.9 (1.5–2.4)</td><td>0.006<sup>b</sup></td></tr><tr><td>RRR</td><td>1.8 (1.5–2.3)</td><td>2.6 (2.2–3.1)</td><td>0.002<sup>b</sup></td></tr></tbody></table>

Data are expressed as median [interquartile range] or median (95% CI). CFR: coronary flow reserve; FFR: fractional flow reserve; IMR: index of microvascular resistance; Pa: mean aortic pressure; Pd: distal pressure; RRR: resistive reserve ratio; TAVI: transcatheter aortic valve implantation; Tnm: transit mean time.

* The Friedman test was used to compare variables (pre-TAVI versus post-TAVI). To control the inflation of the alpha risk due to multiplicity of test, the Benjamini-Hochberg method was used.

a Not significant after adjustments using the Benjamini-Hochberg method.

b Significant after adjustments using the Benjamini-Hochberg method.

### 4.1. Haemodynamic assessment before and after valve implantation

During the TAVI procedure, 29 lesions were assessed at the start of the procedure (pre-TAVI) and shortly after valve implantation (post-TAVI) (Table 3 and Fig. 1). There were no significant differences in median Pd/Pa between pre- and post-TAVI (0.89 [IQR 0.87–0.92] vs 0.89 [IQR 0.88–0.91], respectively; P = 0.18). FFR decreased numerically post-TAVI, from 0.83 (95% CI 0.79–0.84) pre-TAVI to 0.81 (95% CI 0.78–0.83) post-TAVI (P = 0.039) with a mean deviation of –0.01 (minimum 0.06; maximum –0.10)). Hyperaemic Tnm became numerically shorter post-TAVI, from 0.27 seconds (95% CI 0.19–0.35) pre-TAVI to 0.20 seconds (95% CI 0.18–0.27) post-TAVI (P = 0.039) (Fig. 1A). The median IMR decreased numerically (from 14 [IQR 10–19] pre-TAVI to 11 [IQR 9–18] post-TAVI; P = 0.25; normal value < 25). However, RRR increased significantly, from 1.8 (95% CI 1.5–2.3) pre-TAVI to 2.6 (95% CI 2.2–3.1) post-TAVI (P = 0.002) (Fig. 1B), while basal microvascular resistance increased numerically, from 24 (95% CI 21–35) pre-TAVI to 32 (95% CI 23–45) post-TAVI (P = 0.048) (Fig. 1C). Finally, CFR increased significantly, from 1.5 (95% CI 1.2–1.7) pre-TAVI to 1.9 (95% CI 1.5–2.4) post-TAVI (P = 0.006; normal value ≥ 2) (Fig. 1D).
<figure><img src="image_4.png" /><figcaption>**Fig. 1.** Changes in haemodynamics after valve implantation.* The following parameters are presented before TAVI (pre-TAVI) and immediately after TAVI (post-TAVI): A. hyperaemic Tnm, B. RRR, C. basal microvascular resistance and D. CFR. \*The Friedman test was used to compare variables pre- and post-TAVI. To control the inflation of the alpha risk due to multiplicity of test, the Benjamini-Hochberg method was used. †Not significant after adjustments using the Benjamini-Hochberg method. ‡Significant after adjustments using the Benjamini-Hochberg method. CFR: coronary flow reserve; RRR: resistive reserve ratio; TAVI: transcatheter aortic valve implantation; Tnm: transit mean time.</figcaption></figure>

## 4.2. Patient evaluation at follow-up

Twenty-one patients underwent a repeat coronary angiography during follow-up. The median duration of follow-up was 5.4 [IQR 4.8–5.7] months. Eight patients were excluded from the analysis because they could not have a new physiology study after TAVI. Two patients were lost to follow-up due to an unfavourable geriatric course (patients with loss of autonomy); three patients were treated with angioplasty of the target lesion during TAVI, as decided by the operator, based on a positive FFR measurement; one patient had a lesion with negative FFR > 0.95, and the operator deemed it futile to reassess this lesion, so medical management was chosen; one patient could not have an FFR measurement because of difficult coronary access, and was treated medically after a myocardial perfusion scintigraphy revealed no significant ischaemia related to the target lesion; and one patient had a missing assessment due to Coroventis software failure.

At follow-up, the mean gradient of the aortic bioprosthesis was 13.1 ± 3.2 mmHg. No residual leak was observed except in eight patients (38.1%) who had a minimal paravalvular leak. Two patients (9.5%) still suffered from angina compared to six (28.6%) before TAVI.

When the haemodynamics of the 21 lesions were reassessed at follow-up (Table 4 and Fig. 2), there were significant increases in median hyperaemic Pd and Pa values (from 54 [IQR 44–66] mmHg pre-TAVI to 72 [IQR 55–83] mmHg at follow-up; Fig. 2A and from 65

[IQR 52–77] mmHg pre-TAVI to 88 [IQR 71–95] mmHg at follow-up; Fig. 2B; both *P* < 0.001), but no differences were found for resting pressures. Median FFR decreased numerically immediately after valve implantation (from 0.82 [IQR 0.78–0.85] pre-TAVI to 0.81 [IQR 0.77–0.83] post-TAVI; *P* = 0.039) and then increased numerically during follow-up (to 0.83 [IQR 0.79–0.85]; *P* = 0.66) (Fig. 2C). There was no significant difference between median CFR measured pre-TAVI, post-TAVI and at follow-up (1.5 [IQR 1.1–2.0] pre-TAVI, 1.9 [IQR 1.4–2.7] post-TAVI and 2.1 [IQR 1.1–2.6] at follow-up; *P* = 0.23), just as there were no significant differences in the other variables (hyperaemic Tnm, basal microvascular resistance and RRR). However, median IMR values were numerically lower immediately after TAVI before increasing numerically again at follow-up (from 14 [IQR 10–19] pre-TAVI down to 11 [IQR 9–15] post-TAVI and up to 15 [IQR 10–32] at follow-up; *P* = 0.056). Nevertheless, only 3/21 patients (14.3%) had an IMR > 25, indicating microvascular impairment during hyperaemia.

## 4.3. FFR reclassification after TAVI

Prior to TAVI, 9/21 lesions (42.9%) were classified as positive (FFR ≤ 0.8). For these positive lesions, there was a numerical decrease in median FFR immediately after TAVI, followed by a numerical increase at follow-up (0.78 [IQR 0.74–0.79] pre-TAVI, 0.77 [IQR 0.70–0.81] post-TAVI, 0.80 [IQR 0.76–0.87] at follow up; *P* = 0.055) (Fig. 3A). Of note, 4/9 lesions (44.4%) with positive FFR
<table><caption>**Table 4**
Haemodynamics at follow up.</caption><thead><tr><th rowspan="2"></th><th colspan="3">Patients with follow-up (n = 21)</th><th colspan="3">P*</th></tr><tr><th>Pre-TAVI</th><th>Post-TAVI</th><th>Follow-up</th><th>3-way</th><th>Post- vs pre-TAVI*</th><th>Follow-up vs pre-TAVI*</th></tr></thead><tbody><tr><td>Basal Pd (mmHg)</td><td>71 [53-78]</td><td>75 [61-88]</td><td>89 [71-96]</td><td>0.061</td><td>-</td><td>-</td></tr><tr><td>Basal Pa (mmHg)</td><td>82 [62-85]</td><td>84 [70-101]</td><td>96 [78-105]</td><td>0.12</td><td>-</td><td>-</td></tr><tr><td>Pd/Pa</td><td>0.89 [0.86-0.92]</td><td>0.89 [0.88-0.90]</td><td>0.92 [0.89-0.93]</td><td>0.32</td><td>-</td><td>-</td></tr><tr><td>Pd hyperaemia (mmHg)</td><td>54 [44-66]</td><td>57 [46-64]</td><td>72 [55-83]</td><td>&lt;0.001<sup>b</sup></td><td>0.33</td><td>&lt;0.001<sup>b</sup></td></tr><tr><td>Pa hyperaemia (mmHg)</td><td>65 [52-77]</td><td>74 [57-79]</td><td>88 [71-95]</td><td>&lt;0.001<sup>b</sup></td><td>0.083</td><td>&lt;0.001<sup>b</sup></td></tr><tr><td>FFR</td><td>0.82 [0.78-0.85]</td><td>0.81 [0.77-0.83]</td><td>0.83 [0.79-0.85]</td><td>0.029<sup>a</sup></td><td>0.039<sup>a</sup></td><td>0.66</td></tr><tr><td>Tnm basal (s)</td><td>0.37 [0.29-0.74]</td><td>0.36 [0.28-0.93]</td><td>0.53 [0.23-0.74]</td><td>0.98</td><td>-</td><td>-</td></tr><tr><td>Tnm hyperaemia (s)</td><td>0.28 [0.15-0.46]</td><td>0.20 [0.14-0.30]</td><td>0.24 [0.16-0.44]</td><td>0.087</td><td>-</td><td>-</td></tr><tr><td>Basal microvascular resistance</td><td>27 [19-38]</td><td>30 [21-66]</td><td>48 [22-56]</td><td>0.36</td><td>-</td><td>-</td></tr><tr><td>IMR</td><td>14 [10-19]</td><td>11 [9-15]</td><td>15 [10-32]</td><td>0.056</td><td>-</td><td>-</td></tr><tr><td>CFR</td><td>1.5 [1.1-2.0]</td><td>1.9 [1.4-2.7]</td><td>2.1 [1.1-2.6]</td><td>0.23</td><td>-</td><td>-</td></tr><tr><td>RRR</td><td>1.8 [1.4-2.6]</td><td>2.7 [2.2-3.5]</td><td>2.5 [1.3-3.5]</td><td>0.23</td><td>-</td><td>-</td></tr></tbody></table>

Data are expressed as median [interquartile range]. CFR: coronary flow reserve; FFR: fractional flow reserve; IMR: index of microvascular resistance; Pa: mean aortic pressure; Pd: distal pressure; TAVI: transcatheter aortic valve implantation; Tnm: transit mean time; RRR: resistive reserve ratio.

* The Friedman test was used to compare variables. If no significant difference was found between the three groups, P-values for post- vs pre-TAVI and follow-up vs pre-TAVI are not reported. To control the inflation of the alpha risk due to multiplicity of test, the Benjamini-Hochberg method was used.

a Not significant after adjustments using the Benjamini-Hochberg method.

b Significant after adjustments using the Benjamini-Hochberg method.

<figure><img src="image_5.png" /><figcaption>**Fig. 2.** Changes in pressure hyperaemic parameters after valve implantation and at follow-up.* The following parameters are presented before TAVI (pre-TAVI), immediately after TAVI (post-TAVI) and at follow-up: A. Pd in hyperaemia, B. Pa in hyperaemia and C. FFR. In panel C, each point represents one FFR value per lesion. *The Friedman test was used to compare variables (all groups/pre-TAVI versus post-TAVI/pre-TAVI versus follow-up). To control the inflation of the alpha risk due to multiplicity of test, the Benjamini-Hochberg method was used. †Not significant after adjustments using the Benjamini-Hochberg method. ‡Significant after adjustments using the Benjamini-Hochberg method. FFR: fractional flow reserve; Pa: mean aortic pressure; Pd: distal pressure; TAVI: transcatheter aortic valve implantation.</figcaption></figure>
<figure><img src="image_6.png" /><figcaption>**Fig. 3.** Changes in FFR classification at follow up. Evolution of A. positive and B. negative FFR values from baseline before TAVI (pre-TAVI) to immediately after TAVI (post-TAVI) and to follow-up. The Friedman test was used to compare variables (all groups/pre-TAVI versus post-TAVI/pre-TAVI versus follow-up). Results were non-significant hence only one *P*-value is indicated. FFR: fractional flow reserve; TAVI: transcatheter aortic valve implantation.</figcaption></figure>

values prior to TAVI were reclassified as negative at follow-up. A similar numerical trend involving a decrease in median FFR post-TAVI and an increase at follow-up was observed overall for the 12 lesions (57.1%) that were classified as negative before TAVI (0.84 [IQR 0.83–0.86] pre-TAVI, 0.82 [IQR 0.80–0.84] post-TAVI, 0.83 [IQR 0.82–0.84] at follow-up; *P* = 0.055; Fig. 3B). Only 1/12 lesions (8.3%) that were negative before TAVI was reclassified as positive at follow-up (0.86 pre-TAVI, 0.82 post-TAVI, 0.45 at follow-up). This patient had an intermediate lesion of the middle LAD and was admitted to the hospital for unstable angina 3.6 months after TAVI. Coronary angiography and visual assessment revealed a progression of the stenosis from 50% pre-TAVI to 70%, which was treated with angioplasty and stenting. Based on the operator's visual assessment, the other lesions were angiographically similar to those seen during the TAVI procedure.

No complications related to the continuous injection of intra-venous adenosine were reported, and procedure tolerance was good. During post-procedure rhythm monitoring in the intensive care unit, four patients (13.8%) demonstrated high-grade conduc-tive disorders and underwent pacemaker implantation. In two cases (6.9%), coronary re-access was deemed difficult.

**5. Discussion**

Our study in patients with stable CAD and severe AS showed an immediate improvement in coronary microcirculation following TAVI, which was not sustained at follow-up (median 5.4 months). Marginal changes were observed in FFR immediately after valve replacement and at follow-up, in line with the results of previous larger studies [24,26,28].
In patients with severe AS, CFR and microvascular resistance reserve are impaired through a compensatory mechanism of increased resting flow maintaining adequate perfusion at rest, but not during hyperaemia [29]. Immediately after valve implantation, we observed a significant improvement in median CFR (from 1.5 pre-TAVI to 1.9 post-TAVI). Despite the impaired CFR, the response of the microcirculation to hyperaemia appeared to be preserved, with only three patients having an IMR > 25. The RRR parameter, reflecting microvascular reserve, also improved following valve implantation through an increase in microvascular resistances at rest, re-establishing a greater differential with lower resistances during hyperaemia and mechanically increasing microvascular reserve. Similar to the patients with chest pain and no coronary obstruction described by Nardone et al. [30], the patients with severe AS may have a 'low CFR with low IMR' profile: microvascular reserve is altered by abnormally low resting resistances impairing CFR. Ahmad et al. [31] reported that the increase in microvascular reserve after TAVI is independent of the severity of the concomitant CAD. Thus, the observed increase in CFR in our study most likely results from a combination of greater coronary flow in hyperaemia and enhanced microvascular reserve through modification of the rest-to-hyperaemia resistance ratio. This may contribute to symptom relief in patients reporting chest pain, regardless of the severity of CAD.

However, the changes observed immediately following bioprosthesis deployment were no longer significant at the follow-up assessment. The immediate haemodynamic impact of TAVI on coronary reserve and microcirculation is most likely a long-term phenomenon, but this was not confirmed by our study, which lacked statistical power because of the small number of subjects included and the loss of nearly one-third of the patients during follow-up. Another hypothesis is that reverse myocardial remodelling after aortic obstruction removal could take longer than 6 months to develop and our physiological reassessment may have been performed too early after the procedure to detect a significant difference. It is also possible that irreversible myocardial lesions may have permanently altered the coronary reserve and microvascular function in some patients, thus precluding seeing an overall improvement. Larger and longer studies will be necessary to confirm the long-term effect of TAVI on the microcirculation.

Immediately after aortic valve release, median FFR values exhibited a small decrease (from 0.83 to 0.81). This result was independent of the FFR positivity threshold before the procedure, and the decrease was not limited to patients with FFR-positive values, as reported by Pesarini et al. [26]. The patients in that study had less severe coronary stenosis (40% vs 55.9%) and higher pre-TAVI FFR (0.89 versus 0.83), which may have resulted in the observed difference. Our study may have been too small to fully assess the impact of pre-TAVI FFR positivity on post-TAVI values but it supports minimal changes in FFR immediately after TAVI as reported in previous studies [24,26]. In fact, the initial decrease seen for FFR immediately after TAVI was not sustained at follow-up, and the FFR value at follow-up was similar to the pre-TAVI value. These findings align with those reported by Stundl et al. [24] and Sabbah et al. [28] who compared the evolution of FFR measurements for the same

lesions 6 weeks and 6 months after TAVI, respectively, and found no significant differences with measurements performed before TAVI. In contrast, in a study using intra-coronary Doppler flow to assess CAD, Vendrik et al. [25] reported a significant decrease in median FFR assessed 6 months after TAVI, from 0.85 to 0.71, but their cohort was very small (13 coronary lesions), which may have caused the discrepancy.

Regarding individual lesions, 4/9 lesions that were FFR-positive prior to TAVI were no longer positive at 6-month follow-up, and 1/12 lesions that were FFR-negative became positive, resulting in a higher rate of reclassification in our study than reported by Sabbah et al. [28]. In this sub-study of the large randomized controlled Third Nordic Aortic Valve Intervention (NOTION-3) trial, approximately 10% of patients with untreated CAD showed FFR values crossing the 0.80 cut-off when comparing pre-TAVI and 6-month post-TAVI measurements [28]. Our results, which did not achieve statistical significance, may be due to sampling variability. Nevertheless, FFR showed a minimal decrease after valve implantation with limited clinical significance, supporting its reproducibility to guide revascularization in patients with severe AS.

The main limitation of our study is the small number of included patients, limiting the statistical power of the analysis, especially when attempting to control for alpha risk inflation. The large post-TAVI dropout (eight patients) may have induced a selection bias and limit the interpretation of the results at follow-up. It also restricted our ability to perform multivariable analyses to assess the impact of cofactors on physiological outcomes. Additionally, we lack follow-up echocardiographic data for some patients, and no magnetic resonance imaging tests were performed in this population, which limits our ability to evaluate reverse myocardial remodelling or quantify myocardial mass reduction following TAVI. While we considered our sample of lesions to be globally homogeneous (with almost all lesions involving LAD), this focus may overlook important outcomes related to other vessels, especially the right coronary artery, due to the limited number of lesions in that territory.

Our measurements obtained by intracoronary thermodilution could be biased due to the use of bolus injections rather than continuous saline infusions, which appears to have better reproducibility in CFR and IMR measurements [32]. Bolus thermodilution only allows for the calculation of indexes and ratios based on equations derived from measured pressures and Tnm, without providing a true estimate of absolute coronary flow. In our experience, it can be difficult to obtain reproducible Tnm measurements. Tnm values may be influenced by the quality of the manual bolus injection and the stability of the catheter guide in the coronary ostium, and more than three boluses can be necessary to obtain reproducible results.

## 6. Conclusions

In patients with stable CAD and severe AS, TAVI improved the coronary microvascular function by inducing an increase in CFR and RRR. The FFR assessment showed an immediate decrease after valve implantation and a subsequent return to preoperative value at short-term follow-up, with limited impact on the indication for myocardial revascularization (Central illustration).
TAVI improves microcirculation

<figure><img src="image_7.png" /></figure>

<figure><img src="image_8.png" /></figure>

<figure><img src="image_9.png" /></figure>

<figure><img src="image_10.png" /></figure>

**Central Illustration.** TAVI in patient with stable CAD. *Significant after adjustment for multiplicity. CFR: coronary flow reserve; FFR: fractional flow reserve; IMR: index of microvascular resistance; RRR: resistive reserve ratio; TAVI: transcatheter aortic valve implantation.
## Sources of funding

This observational study is an academic trial supported by the CHU de Nantes - Institut du Thorax - France.

## Authorship contributions

QB and TM designed the trial and wrote the protocol, QB and TS performed the statistical analysis, AP submitted the protocol to the regulatory authorities, QB wrote the article, RLR and P-GP assisted with the drafting of the manuscript, and PG, VL and JP participated in enrolling patients.

## Data sharing statement

All requests to share data must be addressed to the corresponding author.

## Acknowledgements

This study was supported by the CHU Nantes.

## Disclosure of interest

The authors declare that they have no competing interest.

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