Muhammad Sabbah

BACKGROUND: Optimal treatment of coronary artery disease in patients undergoing transcatheter aortic valve implantation remains debated. Here, our aim was to analyze the impact of the diameter and location of coronary stenosis on outcomes in patients undergoing percutaneous coronary intervention (PCI) with transcatheter aortic valve implantation. METHODS: This study was a prespecified subanalysis of the NOTION-3 trial (Nordic Aortic Valve Intervention), which randomized patients with severe symptomatic aortic stenosis and physiologically significant stable coronary artery disease to receive either PCI or conservative treatment of coronary artery disease with transcatheter aortic valve implantation. In this substudy, patients were stratified according to diameter stenosis (P for interaction=0.051). PCI reduced major adverse cardiovascular events in case of proximal stenosis (26% versus 38%; hazard ratio, 0.61 [95% CI, 0.40–0.93]), although the difference in effect remained nonsignificant when compared with patients with nonproximal stenosis (28% versus 32%; hazard ratio, 0.91 [95% CI, 0.52–1.61]; P for interaction=0.27). CONCLUSIONS: The beneficial effect of PCI in patients undergoing transcatheter aortic valve implantation with physiologically significant stable coronary artery disease was seemingly pronounced in patients with high-grade stenosis, while stenosis location was not found to modify the outcome despite an almost similar beneficial effect with PCI in patients with proximal stenosis.

The benefit of percutaneous coronary intervention (PCI) in patients with stable coronary artery disease and severe aortic stenosis who are undergoing transcatheter aortic-valve implantation (TAVI) remains unclear. In an international trial, we randomly assigned, in a 1:1 ratio, patients with severe symptomatic aortic stenosis and at least one coronary-artery stenosis with a fractional flow reserve of 0.80 or less or a diameter stenosis of at least 90% either to undergo PCI or to receive conservative treatment, with all patients also undergoing TAVI. The primary end point was a major adverse cardiac event, defined as a composite of death from any cause, myocardial infarction, or urgent revascularization. Safety, including bleeding events and procedural complications, was assessed. A total of 455 patients underwent randomization: 227 to the PCI group and 228 to the conservative-treatment group. The median age of the patients was 82 years (interquartile range, 78 to 85), and the median Society of Thoracic Surgeons-Procedural Risk of Mortality score (on a scale from 0 to 100%, with higher scores indicating a greater risk of death within 30 days after the procedure) was 3% (interquartile range, 2 to 4). At a median follow-up of 2 years (interquartile range, 1 to 4), a major adverse cardiac event (primary end point) had occurred in 60 patients (26%) in the PCI group and in 81 (36%) in the conservative-treatment group (hazard ratio, 0.71; 95% confidence interval [CI], 0.51 to 0.99; P = 0.04). A bleeding event occurred in 64 patients (28%) in the PCI group and in 45 (20%) in the conservative-treatment group (hazard ratio, 1.51; 95% CI, 1.03 to 2.22). In the PCI group, 7 patients (3%) had PCI procedure-related complications. Among patients with coronary artery disease who were undergoing TAVI, PCI was associated with a lower risk of a composite of death from any cause, myocardial infarction, or urgent revascularization at a median follow-up of 2 years than conservative treatment. (Funded by Boston Scientific and the Danish Heart Foundation; NOTION-3 ClinicalTrials.gov number, NCT03058627.).

It is widely accepted that severe aortic valve stenosis (AS) can cause exhaustion of coronary flow reserve (CFR), leading to angina pectoris despite the absence of obstructive coronary artery disease. However, it is not established whether CFR is uniformly affected in the left and right coronary arteries. We addressed the differences in coronary physiology between the left anterior descending artery (LAD) and right coronary artery (RCA) in patients with severe AS before aortic valve replacement, by performing pair-wise comparisons of coronary flow reserve (CFR), fractional flow reserve (FFR), absolute hyperemic flow (Q), and minimal microvascular resistance (R_μ) in the LAD and RCA using intracoronary bolus and continuous saline thermodilution techniques (1). The patients in this analysis represent a subset from a previously published cohort in which the physiology of both the LAD and RCA was evaluated (1). Wilcoxon's signed rank test and paired t-test were used to test the differences in medians and means, respectively. Pearson's correlation coefficient was used to test the relationship between the difference in RCA–LAD CFR and left ventricular mass. Two-tailed p-values 2 with mean and peak gradients of 56 ± 15 mmHg and 87 ± 24 mmHg, respectively. Left ventricular hypertrophy (LVH) was present in 61% of patients (2). CFR in the LAD was significantly lower than in the RCA (Table 1). Although FFR was lower in the LAD than that in the RCA, the difference in CFR between the LAD and RCA remained statistically significant when using CFR adjusted for epicardial pressure loss (i.e., CFR divided by FFR, Table 1). There was no correlation between the absolute RCA–LAD CFR difference and the left ventricular mass indexed to body surface area, r = −0.011, p = 0.97. The resting transit time was significantly shorter in the LAD compared with that in the RCA, whereas hyperemic transit times were not significantly different (Table 1). Interestingly, absolute hyperemic flow and minimal microvascular resistance in the LAD and RCA were not significantly different (Table 1). Table 1. Paired measurements of coronary physiological indices in the left anterior descending and right coronary artery in patients with severe aortic stenosis. In healthy subjects, the coronary vascular bed is organized such that CFR is similar in the overall territory of all coronary arteries (3). The main finding of this study is that in severe AS, CFR is lower in the LAD compared with that in the RCA. This difference was not due to a difference in epicardial disease burden. Instead, our results indicate a higher resting flow in the LAD compared with that in the RCA, as shown once before with a Doppler-based approach (4). A possible explanation for this is that a proportion of RCA flow supplies the right ventricle which escapes the impact of AS, whereas the LAD exclusively supplies the pressure-loaded left ventricle and is thus taxed with a higher resting flow. In our previous work, we have shown that CFR in the LAD significantly increases 6 months after aortic valve replacement (5). Although changes in the RCA were not assessed in that study, it is conceivable that aortic valve replacement ultimately evens out the differences in CFR between the LAD and RCA found in this study. In summary, CFR in the LAD is significantly lower than that in the RCA in patients with severe AS and right-dominant coronary systems. The difference is driven by a higher resting flow in the LAD compared with that in the RCA. The raw data supporting the conclusions of this article will be made available by the authors upon reasonable request. The studies involving human participants were reviewed and approved by Videnskabsetisk Komité, Region Hovedstaden, Denmark. The patients/participants provided their written informed consent to participate in this study. MS contributed to the idea and drafted the manuscript. TE, JL, and NO contributed to the text and statistical analysis and revised the manuscript critically. All authors contributed to the article and approved the submitted version. This work was supported by the BRIDGE—Translational Excellence Programme (bridge.ku.dk) at the Faculty of Health and Medical Sciences, University of Copenhagen, funded by the Novo Nordisk Foundation (grant agreement no. NNF20SA0064340). The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. 1. Sabbah M, Olsen NT, Minkkinen M, Holmvang L, Tilsted H, Pedersen F, et al. Microcirculatory function in nonhypertrophic and hypertrophic myocardium in patients with aortic valve stenosis. J Am Heart Assoc. (2022) 11:e025381. doi: 10.1161/JAHA.122.025381 PubMed Abstract | CrossRef Full Text | Google Scholar 2. Kawel-Boehm N, Hetzel SJ, Ambale-Venkatesh B, Captur G, Francois CJ, Jerosch-Herold M, et al. Reference ranges (“normal values”) for cardiovascular magnetic resonance (CMR) in adults and children: 2020 update. J Cardiovasc Magn Reson. (2020) 22:87. doi: 10.1186/S12968-020-00683-3 PubMed Abstract | CrossRef Full Text | Google Scholar 3. Kern MJ, Bach RG, Mechem CJ, Caracciolo EA, Aguirre FV, Miller LW, et al. Variations in normal coronary vasodilatory reserve stratified by artery, gender, heart transplantation and coronary artery disease. J Am Coll Cardiol. (1996) 28:1154–60. doi: 10.1016/S0735-1097(96)00327-0 PubMed Abstract | CrossRef Full Text | Google Scholar 4. Marcus ML, Doty DB, Hiratzka LF, Wright CB, Eastham CL. Decreased coronary reserve. N Engl J Med. (1982) 307:1362–6. doi: 10.1056/nejm198211253072202 PubMed Abstract | CrossRef Full Text | Google Scholar 5. Sabbah M, Olsen NT, Holmvang L, Tilsted H-H, Pedersen F, Joshi FR, et al. Long-term changes in coronary physiology after aortic valve replacement. EuroIntervention. (2023) 18:1156–64. doi: 10.4244/EIJ-D-22-00621 CrossRef Full Text | Google Scholar Keywords: coronary flow reserve/methods, coronary physiology, aortic stenosis, thermodilution, microvascular Citation: Sabbah M, Engstrøm T, Olsen NT and Lønborg J (2023) Variation in left and right coronary artery physiology in patients with severe aortic stenosis. Front. Cardiovasc. Med. 10:1227532. doi: 10.3389/fcvm.2023.1227532 Received: 23 May 2023; Accepted: 17 July 2023; Published: 3 August 2023. Edited by: Reviewed by: © 2023 Sabbah, Engstrøm, Olsen and Lønborg. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. *Correspondence: Muhammad Sabbah muhammadsabbah.ms@gmail.com

Invasive pressure indices in aortic stenosis: the key role of resting flow after valve replacement

Background: Left ventricular hypertrophy (LVH) has often been supposed to be associated with abnormal myocardial blood flow and resistance. The aim of this study was to evaluate and quantify the physiological and pathological changes in myocardial blood flow and microcirculatory resistance in patients with and without LVH attributable to severe aortic stenosis. Methods and Results: Absolute coronary blood flow and microvascular resistance were measured using a novel technique with continuous thermodilution and infusion of saline. In addition, myocardial mass was assessed with cardiac magnetic resonance imaging. Fifty‐three patients with aortic valve stenosis were enrolled in the study. In 32 patients with LVH, hyperemic blood flow per gram of tissue was significantly decreased compared with 21 patients without LVH (1.26±0.48 versus 1.66±0.65 mL·min ⁻¹ ·g ⁻¹ ; P =0.018), whereas minimal resistance indexed for left ventricular mass was significantly increased in patients with LVH (63 [47–82] versus 43 [35–63] Wood Units·kg; P =0.014). Conclusions: Patients with LVH attributable to severe aortic stenosis had lower hyperemic blood flow per gram of myocardium and higher minimal myocardial resistance compared with patients without LVH.

Background: Patients with severe aortic stenosis frequently have coexisting coronary artery disease. Invasive hyperemic and nonhyperemic pressure indices are used to assess coronary artery disease severity but have not been evaluated in the context of severe aortic stenosis. Methods: We compared lesion reclassification rates of fractional flow reserve (FFR) and resting full-cycle ratio (RFR) measured before and 6 months after transcatheter aortic valve implantation using the conventional clinical cutoffs of ≤0.80 for FFR and ≤0.89 for RFR. This was a substudy of the ongoing NOTION-3 trial (Third Nordic Aortic Valve Intervention). Two-dimensional quantitative coronary analysis was used to assess changes in angiographic lesion severity. Results: Forty patients were included contributing 50 lesions in which FFR was measured. In 32 patients (36 lesions), RFR was also measured. There was no significant change in diameter stenosis from baseline to follow-up, 49.8% (42.9%–57.1%) versus 52.3% (43.2%–57.8%), P =0.50. RFR improved significantly from 0.88 (0.83%–0.93) at baseline to 0.92 (0.83–0.95) at follow-up, P =0.003, whereas FFR remained unchanged, 0.84 (0.81–0.89) versus 0.86 (0.78–0.90), P =0.72. At baseline, 11 out of 50 (22%) lesions were FFR-positive, whereas 15 out of 50 (30%) were positive at follow-up, P =0.219. Corresponding numbers for RFR were 23 out of 36 (64%) at baseline and 12 out of 36 (33%) at follow-up, P =0.003. Conclusions: In patients with severe aortic stenosis, physiological assessment of coronary lesions with FFR before transcatheter aortic valve implantation leads to lower reclassification rate at 6-month follow-up, compared with RFR.