ORIGINAL RESEARCH published: 01 April 2022 doi: 10.3389/fcvm.2022.852954 Prognosis of Paradoxical Low-Flow Low-Gradient Aortic Stenosis: A Severe, Non-critical Form, With Surgical Treatment Benefits Edited by: Laura Galian-Gay 1 , Roxana Andreina Escalona Silva 1 , Gisela Teixidó-Turà 1 , Ronak Rajani, Guillem Casas 1 , Elena Ferrer-Sistach 2 , Cristina Mitroi 3 , Susana Mingo 3 , Guy’s and St Thomas’ NHS Foundation Trust, United Kingdom Vanessa Monivas 3 , Daniel Saura 4 , Bàrbara Vidal 5 , Livia Trasca 5 , Sergio Moral 6 , Francisco Calvo 7 , Maria Castiñeira Busto 7 , Violeta Sánchez 8 , Ariana Gonzalez 9 , Reviewed by: Gabriela Guzman 10 , Marta Noris Mora 11 , MiguelÁngel Arnau Vives 12 , Jesús Peteiro 13 , Choon Hwai Yap, Alberto Bouzas 13 , Aleksandra Mas-Stachurska 14 , Teresa González-Alujas 1 , Imperial College London, United Kingdom Laura Gutiérrez 1 , Rubén Fernandez-Galera 1 , Filipa Valente 1 , Andrea Guala 1 , Chiara De Biase, Aroa Ruiz-Muñoz 1 , Cesar Augusto Sao Avilés 1 , José F. Rodríguez Palomares 1 , Centro Sanitario Locale Napoli 1 Ignacio Ferreira 1* and Artur Evangelista 1* Centro, Italy 1 Department of Cardiology, Hospital Universitari Vall d’Hebron, CIBER-CV, Universitat Autònoma de Barcelona, Barcelona, *Correspondence: Spain, 2 Department of Cardiology, Hospital Universitari Germans Tries i Pujol, Badalona, Spain, 3 Department of Cardiology, Artur Evangelista Hospital Puerta de Hierro - Majadahonda, Madrid, Spain, 4 Department of Cardiology, CIBER-CV, Hospital Clínico arturevangelistamasip@gmail.com Universitario Virgen de la Arrixaca, Murcia, Spain, 5 Department of Cardiology, Hospital Clínic de Barcelona, Barcelona, Spain, Ignacio Ferreira 6 Department of Cardiology, Hospital Josep Trueta, Girona, Spain, 7 Department of Cardiology, Hospital Alvaro Cunqueiro, nachoferreira@secardiologia.es Vigo, Spain, 8 Department of Cardiology, CIBER-CV, Hospital Universitario 12 de Octubre, Madrid, Spain, 9 Department of Cardiology, Hospital Ramón y Cajal, Madrid, Spain, 10 Department of Cardiology, Hospital Universitario La Paz, Madrid, Specialty section: Spain, 11 Department of Cardiology, Hospital Universitario Son Espases, IdISBa, Mallorca, Spain, 12 Department of Cardiology, This article was submitted to Hospital Universitario y Politécnico La Fe, Valencia, Spain, 13 Department of Cardiology, CIBER-CV, Complexo Hospitalario Heart Valve Disease, Universitario A Coruña, Coruña, Spain, 14 Department of Cardiology, Hospital del Mar – Parc de Salut Mar, Barcelona, Spain a section of the journal Frontiers in Cardiovascular Medicine Objectives: To determine the risk of mortality and need for aortic valve replacement Received: 11 January 2022 Accepted: 07 February 2022 (AVR) in patients with low-flow low-gradient (LFLG) aortic stenosis (AS). Published: 01 April 2022 Methods: A longitudinal multicentre study including consecutive patients with severe Citation: AS (aortic valve area [AVA] < 1.0 cm2 ) and normal left ventricular ejection fraction (LVEF). Galian-Gay L, Escalona Silva RA, Teixidó-Turà G, Casas G, Patients were classified as: high-gradient (HG, mean gradient ≥ 40 mmHg), normal-flow Ferrer-Sistach E, Mitroi C, Mingo S, low-gradient (NFLG, mean gradient < 40 mmHg, indexed systolic volume (SVi) > 35 Monivas V, Saura D, Vidal B, Trasca L, Moral S, Calvo F, Castiñeira Busto M, ml/m²) and LFLG (mean gradient < 40 mmHg, SVi ≤ 35 ml/m²). Sánchez V, Gonzalez A, Guzman G, Results: Of 1,391 patients, 147 (10.5%) had LFLG, 752 (54.1%) HG, and 492 (35.4%) Mora MN, Arnau Vives M, Peteiro J, Bouzas A, Mas-Stachurska A, NFLG. Echocardiographic parameters of the LFLG group showed similar AVA to the HG González-Alujas T, Gutiérrez L, group but with less severity in the dimensionless index, calcification, and hypertrophy. Fernandez-Galera R, Valente F, Guala A, Ruiz-Muñoz A, Avilés CAS, The HG group required AVR earlier than NFLG (p < 0.001) and LFLG (p < 0.001), Palomares JFR, Ferreira I and with no differences between LFLG and NFLG groups (p = 0.358). Overall mortality was Evangelista A (2022) Prognosis of 27.7% (CI 95% 25.3–30.1) with no differences among groups (p = 0.319). The impact Paradoxical Low-Flow Low-Gradient Aortic Stenosis: A Severe, Non-critical of AVR in terms of overall mortality reduction was observed the most in patients with HG Form, With Surgical Treatment (hazard ratio [HR]: 0.17; 95% CI: 0.12–0.23; p < 0.001), followed by patients with LFLG Benefits. Front. Cardiovasc. Med. 9:852954. (HR: 0.25; 95% CI: 0.13–0.49; p < 0.001), and finally patients with NFLG (HR: 0.29; doi: 10.3389/fcvm.2022.852954 95% CI: 0.20–0.44; p < 0.001), with a risk reduction of 84, 75, and 71%, respectively. Frontiers in Cardiovascular Medicine | www.frontiersin.org 1 April 2022 | Volume 9 | Article 852954 Galian-Gay et al. Low-Flow Low-Gradient Aortic Stenosis Prognosis Conclusions: Paradoxical LFLG AS affects 10.5% of severe AS, and has a lower need for AVR than the HG group and similar to the NFLG group, with no differences in mortality. AVR had a lower impact on LFLG AS compared with HG AS. Therefore, the findings of the present study showed LFLG AS to have an intermediate clinical risk profile between the HG and NFHG groups. Keywords: aortic stenosis, paradoxical low-flow low-gradient, echocardiography, aortic valve surgery, heart valve disease INTRODUCTION the New York Heart Association was ≥ II, or syncope or angina was reported in clinical reports. Follow-up clinical data, such as Degenerative aortic stenosis (AS) is the most common valve the need for surgery or TAVI, status (alive/deceased), and cause disease in developed countries and, owing to aging of the of death (cardiovascular/non-cardiovascular) were also obtained. population, threatens to become a true epidemic in coming AVR was indicated at the participating centers according to decades (1). Paradoxical low-flow low-gradient (LFLG) AS current guideline indications (9). poses diagnostic challenges and uncertainties regarding the true Echocardiographic studies were performed in all patients severity of the disease and appropriate therapeutic decision- by expert imaging cardiologists at the participating centers. making. Initial studies considered LFLG AS to be an entity with Measurements were obtained following European Association of worse prognosis than high-gradient (HG) AS and could thus Cardiovascular Imaging (EACVI) standards and were validated benefit from surgical or percutaneous treatment as or earlier by a senior expert from each center. AVA was calculated than in HG AS (2–4). However, recent meta-analyses questioned through continuity equation. The degree of aortic valve these results, considering that LFLG AS probably behaves in an calcification and stenosis was established semi-quantitatively intermediate manner between moderate and severe AS (5–8). as recommended by current guidelines (10). Patients were The present study aimed to assess, in a large and contemporary classified into 3 groups according to baseline ECG data cohort of patients with AS, the natural history and prognosis of regarding the gradient and indexed systolic volume (SVi) LFLG AS in comparison with HG and normal-flow low-gradient as recommended by current guidelines (10): high-gradient (NFLG) AS, as well as the impact of aortic valve replacement (HG) if mean gradient ≥ 40 mmHg, normal-flow low- (AVR) in each subgroup. gradient (NFLG) if mean gradient <40 mmHg and SVi > 35 ml/m², and LFLG if mean gradient < 40 mmHg and SVi ≤ 35 ml/m². Patients were not involved in the MATERIALS AND METHODS design, conducting, reporting, or dissemination plans of A retrospective longitudinal observational study was conducted our research. of consecutive patients from 14 tertiary hospitals nationwide All analyses were made with Stata software version 13.1. diagnosed between 2008 and 2016 with severe AS (aortic Continuous variables were expressed as mean and SD when valve area (AVA) <1.0 cm²) with left ventricular ejection the normality assumptions were met and as median and fraction (LVEF) ≥ 50% on the transthoracic ECG (Figure 1). interquartile range (IQR) otherwise. Categorical variables were Exclusion criteria were: age <18 years, atrial fibrillation expressed as absolute numbers and percentages. Demographic, or pacemaker rhythm, aortic regurgitation more than mild, echocardiographic, and AVR variables were evaluated among other valvular heart disease more than mild, left ventricular the different groups using ANOVA test, chi-square test, or outflow tract dynamic gradient exceeding a velocity >1 m/s, Fisher’s exact test, as appropriate. Kaplan–Meier analysis was previous heart surgery, suboptimal echocardiographic window, used for time-to-event variables (time-mortality and time-AVR) poor blood pressure control, and comorbidities at baseline and the log-rank test to compare survival and time-AVR curves that could themselves cause an alteration in functional grade among groups. A multivariate Cox regression analysis was used or prognosis (e.g., severe chronic obstructive pulmonary to identify independent variables associated with the response disease [COPD]). variable (predictors of mortality and AVR), such as variables with The approval for the study was obtained from the Ethics statistical significance (p < 0.20) in the univariate analysis or with Committee of the Vall d’Hebron Hospital (PR (AG) 60/2018). significant clinical relevance. The study protocol conformed to the ethical guidelines of the Declaration of Helsinki 1975 as reflected in the Ethics RESULTS Committee approval. Baseline demographic and clinical data were collected. The Baseline Clinical and Demographic presence of coronary artery disease was defined when a history of Characteristics acute myocardial infarction, significant ischaemic or the presence In this study, 1,391 patients with baseline ECG with AVA < of coronary artery disease were documented. The presence of 1 cm² and normal LVEF from 14 tertiary hospitals (Figure 1), baseline symptoms was considered when the functional status of mean age 74.5 (10.9) years and 53.6% women were included. Frontiers in Cardiovascular Medicine | www.frontiersin.org 2 April 2022 | Volume 9 | Article 852954 Galian-Gay et al. Low-Flow Low-Gradient Aortic Stenosis Prognosis with the HG group and similar to the NFLG group (Table 2). Severe valve calcification in the LFLG group was lower than in the HG group and showed no significant differences with the NFLG group. AVR Indication According to AS Subgroups at Baseline In total, 1,248 patients had complete data related to AVR (676 (54.2%) with HG, 450 (36.0%) with NFLG and 122 (9.8%) with LFLG). Throughout the follow-up, 857 patients (68.7%, CI 95% 66.0–71.2) underwent AVR [685 surgery and 172 Transcater Aortic Valve Implantation (TAVI)]: 529 with HG (78.2%, CI 95% 75.0–81.3; median time: 17.7 months, IQR 5.5–43.4 months), 74 with LFLG (60.6%, CI 95% 51.4– 69.4; median time: 41.0 months, IQR 13.6–78.9 months) and 254 with NFLG (56.4%, CI 95% 51.7–61.1; median time: 46.9 months, IQR: 26.0–70.0 months) (Figure 2) with differences among groups in the estimated survival free from AVR that persisted after adjustment for age, smoking, diabetes mellitus, presence of symptoms, and LVEF (p < 0.001). In HG AS, AVR was indicated earlier compared with NFLG (log-rank p < 0.001) and LFLG AS (log-rank p < 0.001). No significant differences were observed between the LFLG and NFLG groups (log-rank p = 0.358). On multivariate analysis, indication of AVR was inversely associated with age (hazard ratio [HR] 0.99, CI 95%: 0.98–0.99; p = 0.002); nevertheless, the presence of symptoms (HR 1.82, 95% CI: 1.57–2.01; p <0.001) and coronary artery disease (HR 1.21, FIGURE 1 | A flowchart of patients participating in the study. AS, aortic 95% CI: 1.03–1.43; p = 0.018) were independently related to AVR stenosis; AVA, aortic valve area; LVEF, left ventricular ejection fraction. indication. Regarding echocardiographic parameters, AVA (AVA < 0.8 cm2 : HR 1.25, 95% CI: 1.04–1.48; p = 0.014), mean gradient (mean gradient ≥ 40 mmHg: HR 1.95, 95% CI: 1.67–2.29, p <0.001), dimensionless index (dimensionless index ≤ 0.25: HR 1, 39, 95% CI: 1.18–1.65, p < 0.001), and LVEF 50–55% (HR 1.52, In the whole cohort, 752 (54.1%) were classified as HG, 492 95% CI: 1.21–1.91, p < 0.001) were also independently associated (35.4%) as NFLG, and 147 (10.5%) as LFLG. No significant to AVR indication (Supplementary Table 1). differences were observed among groups regarding age, sex, or cardiovascular risk factors, except for smoking and body weight (Table 1). The mean total follow-up time was 59.0 Mortality According to AS Subgroup at months (IQR 39.7–82.9 months), with no significant differences Baseline among groups. Overall mortality during follow-up was 27.7% (385 patients, CI 95% 25.3–30.1): 46 of the LFLG group (31.3%, CI 95% 23.9– Baseline Echocardiographic 39.5; median time: 50.8 months, IQR: 29.6–75.8), 205 of the HG Characteristics group (27.3%, CI 95% 24.1–30.6; median time: 56.1 months, IQR: The echocardiographic data of each AS subtype are shown 33.8–83.7), and 134 of the NFLG group (27.2%, CI 95% 23.3– in Table 2. Remarkably, AVA of the LFLG group was similar 31.4; median time: 53.2 months, IQR: 31.0–76.9). Kaplan–Meier to AVA of the HG group [0.74 (0.14) vs. 0.73 (0.16) cm²; survival curves showed no significant differences among groups p = NS] and significantly lower than that of the NFLG (Figure 3, log-rank p = 0.319). Early mortality after AVR (<30 group [0.89 (0.09), p < 0.001]. However, the dimensionless days) was 6.5% (25 patients, CI 95% 1.2–2.6) with no differences index (ratio between LVOT VTI and aortic VTI) value in the among groups. LFLG group was intermediate between the HG group [0.25 Death from cardiovascular cause occurred in 195 cases (14%, (0.06) vs. 0.22 (0.05); p < 0.001] and the NFLG group [0.25 CI 95% 12.2–16.0) representing a 50.6% of overall mortality: 28 (0.06) vs. 0.27 (0.04); p < 0.001], with differences between patients with LFLG (19%, CI 95% 13.0–26.3; median time: 50.9 the HG and NFLG groups also being significant [0.22 (0.05) months, ICR: 32.0–75.9), 95 patients with HG (12.6%, CI 10.3– vs. 0.27 (0.04); p < 0.001]. Left ventricular hypertrophy was 15.2; median time: 56.1 months, ICR: 33.8–83.7), and 72 patients significantly lower in patients of the LFLG group compared with NFLG (14.6%, CI 95% 11.6–18.1; median time: 52.5 months, Frontiers in Cardiovascular Medicine | www.frontiersin.org 3 April 2022 | Volume 9 | Article 852954 Galian-Gay et al. Low-Flow Low-Gradient Aortic Stenosis Prognosis TABLE 1 | Clinical and demographic data according to aortic stenosis (AS) subgroups at baseline. All patients n HG n = 752 NFLG n = 492 LFLG n = 147 p-value = 1,391 (54.1%) (35.4%) (10.5%) Females, n (%) 744 (53.6) 393 (52.3) 272 (55.4) 79 (54.5) 0.560 Age, years [mean (SD), median, IQR] 74.5 (10.9) 74.3 (10.8) 74.4 (11.3) 76.0 (10.4) 0.155 77 (70–82) 76 (69–82) 77 (70–81) 78 (73–82) Body surface area, Kg/m2 1.8 (0.2) 1.8 (0.2) 1.7 (0.2) 1.8 (0.2) 0.834 Weight, Kg 72.7 (13.3) 73.0 (13.3) 71.1 (12.1) 76.6 (15.6) <0.001 Height, cm 160.3 (9.6) 160.6 (9.9) 159.7 (8.8) 160.3 (10.3) 0.264 Hypertension, n (%) 1,120 (80.5) 601 (79.9) 403 (81.9) 116 (78.9) 0.584 Dyslipidaemia, n (%) 799 (57.4) 431 (57.3) 284 (57.7) 84 (57.1) 0.987 Diabetes, n (%) 456 (32.8) 254 (33.8) 147 (29.9) 55 (37.4) 0.157 Smoking status, n (%) 270 (19.4) 169 (22.5) 80 (16.3) 21 (14.3) 0.007 Coronary disease, n (%) 320 (23.0) 165 (22.0) 121 (24.6) 34 (23.1) 0.550 COPD, n (%) 172 (12.4) 93 (12.4) 65 (13.2) 14 (9.5) 0.513 Baseline symptoms, n (%) 777 (55.9) 438 (58.2) 256 (52.0) 83 (56.5) 0.097 Follow-up, months (IQR) 59.0 (39.7–82.9) 59.3 59.4 (43.5–79.8) 55.6 0.286 (38.4–84.6) (36.6–76.5) AS, aortic stenosis; COPD, chronic obstructive pulmonary disease; HG, high gradient; IQR, interquartile range; LFLG, low-flow low-gradient; NFLG, normal-flow low-gradient; SD, standard deviation. For continuous variables mean and SD was expressed [mean (SD)]. TABLE 2 | Echocardiographic data according to the AS subgroup at baseline. All patients HG n = 752 NFLG n = LFLG n = 147 p-value n = 1391 (54.1%) 492 (35.4%) (10.5%) Maximum aortic jet velocity, m/s 4.4 (0.3) 5.1 (0.7) 3.6 (0.3) 3.5 (0.4) 0.035a.b Mean aortic gradient, mmHg 42.0 (14.0) 51.6 (11.5) 31.2 (5.4) 29.2 (6.7) <0.001a.b LVOT, mm 2.04 (0.17) 2.04 (0.17) 2.04 (0.15) 1.97 (0.18) <0.001b.c LVOT VTI, cm 23.3 (4.7) 24 (5.0) 23.6 (3.8) 18.4 (3.7) <0.001a.b SVi, ml/m² 43.2 (9.1) 44.7 (9.6) 44.5 (6.2) 30.8 (3.3) <0.001b.c AVA, cm² 0.79 (0.16) 0.73 (0.16) 0.89 (0.09) 0.74 (0.14) <0.001a.c Dimensionless index 0.24 (0.05) 0.22 (0.05) 0.27 (0.04) 0.25 (0.06) <0.001a.b.c Severe aortic valve calcification, n (%) 717 (54.1) 488 (67.7) 186 (38.7) 4 (35.0) <0.001a.b Bicuspid aortic valve. n (%) 156 (11.5) 88 (11.9) 59 (12.3) 9 (6.5) 0.008b.c LVEDD, mm 46.0 (6.7) 46.3 (6.8) 45.7 (6.0) 45.2 (7.5) 0.059 LVESD, mm 29.0 (6.2) 29.2 (6.2) 28.8 (6.0) 29.2 (6.6) 0.062 IVS, mm 13.7 (2.4) 14.2 (2.4) 13.1 (2.4) 13.4 (2.5) <0.001a.b PW, mm 12.3 (2.1) 12.6 (2.1) 11.8 (2.0) 12.1 (2.2) <0.001a.b LVEF, % 64.8 (7.2) 65.0 (7.3) 64.5 (7.1) 64.6 (7.7) 0.228 LVEF 50–55%, n (%) 63 (4.5%) 31 (4.1) 21 (4.3) 11 (7.5) 0.200 LV mass, g/m² 130.5 (42.5) 139.7 (41.7) 120.9 (41.7) 118.1 (38.8) <0.001a.b E/e’ 14.7 (7.4) 14.6 (8.0) 14.8 (7.3) 14.7 (5.4) 0.881 LA volume, ml 72.5 (36.7) 71.6 (26.0) 73.8 (49.6) 74.0 (40.7) 0.510 AS, aortic stenosis; AVA, aortic valve area; COPD, chronic obstructive pulmonary disease; HG, high gradient; IQR, interquartile range; IVS, interventricular septum; LA, left atrium. LFLG, low-flow low-gradient; LVEDD, left ventricle end diastolic diameter; LVEF, left ventricular ejection fraction; LVESD, left ventricle end systolic diameter; LVOT, left ventricle outflow tract; NFLG, normal-flow low-gradient. PW, posterior wall; SD, standard deviation; SVi, indexed systolic volume; VTI, velocity-time integral. For continuous variables mean and SD was expressed [mean (SD)]. a, significant differences between HG and NFLG; b, significant differences between HG and LFLG; c, significant differences between NFLG and LFLG. ICR: 29.0–76.9), with no significant differences among groups observed among groups (log-rank p = 0.004), with low (Figure 4, log-rank p = 0.061). event-free survival in the HG group compared with the In patients undergoing AVR, no significant differences NFLG group (log-rank p = 0.001), with no significant in mortality were observed among groups (log-rank p = differences between the LFLG and HG groups (log-rank p = 0.612) after adjustment for significant clinical variables and 0.354) or between the LFLG and NFLG groups (log-rank p AVA. However, in non-operated patients, differences were = 0.171). Frontiers in Cardiovascular Medicine | www.frontiersin.org 4 April 2022 | Volume 9 | Article 852954 Galian-Gay et al. Low-Flow Low-Gradient Aortic Stenosis Prognosis FIGURE 2 | Kaplan–Meier aortic valve replacement (AVR)-free survival curves according to AS subtype at baseline. HG, high-gradient; LFLG, low-flow low-gradient; NFLG, normal-flow low-gradient (log-rank p < 0.001). In the multivariate analysis, age (HR 1.06, 95% CI: 1.04– DISCUSSION 1.08; p < 0.001), diabetes mellitus (HR 1.52; 95% CI: 1.23– 1.89; p < 0.001), smoking (HR: 1.77, 95% CI: 1.32–2.37; p In this large multicentre retrospective cohort of consecutive < 0.0001), COPD (HR 1.45, 95% CI: 1.09–1.92; p = 0.010), patients with AS and normal ejection fraction and sinus and the presence of symptoms (HR 1.48, 95% CI: 1.18– rhythm, the prevalence of paradoxical LFLG AS was 10%. 1.85; p = 0.001) were clinical variables associated to overall Echocardiographic parameters showed a similar AVA in mortality (Supplementary Table 2). Echocardiographic variables comparison with HG and NFLG groups, but less severity in independently associated with mortality were mean gradient > the dimensionless index, valve calcification, and LV hypertrophy 50 mmHg (HR 1.56, 95% CI: 1.17–2.08; p = 0.002) and LVEF than in HG AS. However, overall/cardiovascular mortality and 50–55% (HR 1.68, 95% CI: 1.07–2.63; p = 0.023). the impact of AVR on mortality reduction were similar to patients with HG AS. Impact of AVR on Mortality Reduction Overall mortality was higher in those patients who did not undergo AVR. The impact of AVR on mortality reduction in Echocardiographic Characterization of the whole population with AS was significant (HR: 0.22; 95% LFLG AS CI: 0.18–0.28; p < 0.001) after adjustment for significant clinical In the present series, patients with LFLG AS had a similar variables and AVA. AVR reduced mortality risk by 83% in AVA value to the HG group and lower than NFLG group. patients with HG AS (HR: 0.17; 95% CI: 0.12–0.23; p < 0.001), However, in the remaining echocardiographic parameters, such 75% in patients with LFLG (HR: 0.25; 95% CI: 0.13–0.49; p < as left ventricular hypertrophy and degree of valve calcification, 0.001), and 71% in patients with NFLG AS (HR: 0.29; 95% CI: LFLG did not significantly differ from NFLG AS. Interestingly, 0.20–0.44; p < 0.001; Figure 5). the dimensionless index in LFLG AS laid between HG and Frontiers in Cardiovascular Medicine | www.frontiersin.org 5 April 2022 | Volume 9 | Article 852954 Galian-Gay et al. Low-Flow Low-Gradient Aortic Stenosis Prognosis FIGURE 3 | Kaplan–Meier survival curves for overall mortality according to AS subtype at baseline. HG, high-gradient; LFLG, low-flow low-gradient; NFLG, normal-flow low-gradient (log-rank p = 0.319). NFLG AS. Thus, LFLG AS presented intermediate-severity Outcome in LFLG Patients and Protective echocardiographic parameters between HG and NFLG AS. Effect of AVR Other series yielded similar results (4). Clavel et al. in a The risk throughout follow-up of undergoing AVR was higher series of 561 patients with AS, found LFLG patients to for patients with HG, lower in patients with LFLG AS and have significantly lower velocity and transaortic gradients than comparable to patients with NFLG AS, as previously reported HG AS while AVA was practically the same (11). Several (14). Mortality was 27% and no significant differences were studies reported that this entity was associated with small detected between patients with LFLG AS and the other groups. ventricles and a high degree of hypertrophy (2); however, Patients of the three hemodynamic groups who underwent the present LFLG group had a significantly lower degree AVR had a similar prognosis, whereas patients who did of hypertrophy than patients with HG AS but similar to not undergo surgery had higher mortality in the HG group those with NFLG AS. Other studies using echocardiography compared with the NFLG group, with no differences between or CMR stated that patients with LFLG AS do not have the LFLG and HG groups. Different series previously reported a greater degree of hypertrophy than HG AS, but lower poorer survival and a higher rate of events in the LFLG or similar to NFLG AS or moderate AS (4, 5, 12). Few population compared with HG AS (3, 11, 15); however, the studies analyzed the degree of calcification in LFLG AS by trend in the more contemporary series has changed the echocardiography or multidetector CT (MDCT), although this paradigm, suggesting that higher mortality is associated with is currently one of the more recommended approaches to HG AS, with the behavior of LFLG AS being more similar diagnose severe AS (10, 13). Calcification by MDCT may to moderate AS or intermediate between HG and NFLG AS be highly useful in patients with discordant severity data on (8, 16). Recent evidence suggested that moderate forms of echocardiography (13). AS are not as benign as historically assumed, particularly if Frontiers in Cardiovascular Medicine | www.frontiersin.org 6 April 2022 | Volume 9 | Article 852954 Galian-Gay et al. Low-Flow Low-Gradient Aortic Stenosis Prognosis FIGURE 4 | Kaplan–Meier survival curves for cardiovascular mortality according to AS subtype at baseline. HG, high-gradient; LFLG, low-flow low-gradient; NFLG, normal-flow low-gradient (log-rank p = 0.061). FIGURE 5 | Cox survival curves for overall mortality in the population with severe AS according to AVR and AS subtype [(A): HG; (B): LFLG; (C): NFLG)]. AVR, aortic valve replacement. left ventricular dysfunction is present (17). A recent study surgically-treated patients, with surgery being associated with analyzing data from the Australian national echocardiography a significant increase in survival (19). Taking the results database showed mortality in patients with moderate AS to of this study and previous reported findings into account, be similar to severe AS (18). Another contemporary study there may be sufficient reasons to consider AS severity as reported that patients with NFLG who did not undergo moderate-severe when the AVA is between 0.8–1.2 cm2 and surgery had 6.3 times more overall mortality compared with severe when < 0.8 cm2 . In moderate-severe patients with Frontiers in Cardiovascular Medicine | www.frontiersin.org 7 April 2022 | Volume 9 | Article 852954 Galian-Gay et al. Low-Flow Low-Gradient Aortic Stenosis Prognosis AS, other multimodality parameters, such as calcium score dysfunction, to sustain the choice to treat paradoxical LFLG as by CT, exercise test, or left ventricle overall strain could HG AS. help to identify a subgroup of patients in whom AVR would be indicated. Overall, patients with significant AS benefited from LIMITATIONS intervention on the AV, and despite the HG AS group benefited The main limitation of this study was its retrospective nature. the most, both LFLG and NFLG AS also obtained significant In the present series, confirmation of the low-flow state was benefit. Although few studies failed to show this benefit in not requested for inclusion. Exclusion of patients with atrial patients with LFLG AS (5, 20), most series suggested a beneficial fibrillation was considered in the design of the study since the effect of valve replacement in the LFLG population (and even continuity equation may be less accurate in AVA calculation. in NFLG and moderate AS) compared with conservative Calcification of the aortic valve was analyzed following the semi- management (4, 18, 19). Thus, evidence of the effectiveness quantitative approach recommended by the current guidelines, of aggressive treatment (surgical or percutaneous) of AS although the optimal method is cardiac CT. Myocardial strain continues to grow and, though data remain discrepant, the would have added complementary information; however, owing trend is toward a more aggressive approach and in a wider to the multicentre nature of the study and the years of range of the disease. inclusion established, variability of the values depending on the different vendors used would have resulted in difficult result analysis. Mortality Risk Predictors in Patients With Severe AS CONCLUSIONS In this study, patients with AS who died were older, more symptomatic, had more cardiovascular risk factors and a Low-flow low-gradient AS has intermediate echocardiographic smaller AVA. However, the multivariate analysis failed to show severity parameters and clinical outcomes between NFLG and AVA to be independently associated with mortality which HG AS, with lower AVR requirements than HG AS, but with instead was related to age, risk factors (diabetes, smoking, overall mortality and benefits of surgery similar to the other and COPD), symptoms, mean gradient > 50 mmHg, and two haemodynamic groups. Given that patients classified within LVEF from 50–54%. Some studies showed mortality in AS this group benefited significantly from AVR, they should be to be associated with maximum velocity, aortic calcification, followed with caution as in HG AS. The most appropriate option and LVEF. Valvular heart disease guidelines recommended to adequately manage this subgroup may be to maximize the as class I an AVR indication in systolic dysfunction (LVEF accuracy of the echocardiographic evaluation, provide additional < 50%) regardless of the presence of symptoms (9, 21). information through other imaging techniques and determine However, recent studies reported that patients with LVEF < whether there are data supporting the severity of AS or suggestive 55% had poor prognosis (22–24). All these results suggest of incipient ventricular dysfunction, for them to be treated as that the cut-off point of <50% for LVEF could be too low, HG AS. indicating that left ventricular dysfunction is already present when LVEF is between 50 and 60% and, in fact, recent DATA AVAILABILITY STATEMENT guidelines recommend that patients with LVEF < 60% on serial studies and severe AS should undergo surgery (21). The datasets presented in this article are not readily available Cardiac magnetic resonance demonstrated the presence of late because further analyses are still underway for other papers gadolinium enhancement and increased extracellular volume awaiting publication. Requests to access these datasets should be in AS patients with normal ejection fraction, which have directed to LG-G, lauragaliangay@gmail.com. been related to prognosis (25). Other imaging techniques, such as strain by speckle tracking echocardiography can detect patients with subclinical ventricular dysfunction, (26) with ETHICS STATEMENT overall longitudinal strain values < −15% being associated The studies involving human participants were reviewed with worse prognosis (27, 28). Global LV strain values may and approved by CEIm - Comitè d’Ètica d’Investigació amb become one of the markers that will provide additional data medicaments - VHIR. Informed consent was not available due to decide whether or not the patient could have a higher to the retrospective nature of the study. risk and deserves surgery. Given that patients with LFLG AS benefit significantly from AVR, they should be followed with caution, with the accuracy in echocardiographic severity AUTHOR CONTRIBUTIONS evaluation to be maximized to avoid possible errors in SVi quantification. Furthermore, additional information through LG-G, GT-T, GC, and AE designed the study. LG-G, RE, GC, other imaging techniques (myocardial strain, CMR of calcium EF-S, CM, SMi, VM, DS, BV, LT, SM, FC, MC, VS, AGo, GG, score by CT) are likely to be useful to determine whether data MM, MA, JP, AB, AM-S, TG-A, LG, RF-G, FV, and AR-M support the AS severity and/or suggest incipient ventricular contributed to conduction and reporting of the study. LG-G Frontiers in Cardiovascular Medicine | www.frontiersin.org 8 April 2022 | Volume 9 | Article 852954 Galian-Gay et al. Low-Flow Low-Gradient Aortic Stenosis Prognosis and AS performed the statistical analysis. AE, AGu, JFP, and IF ACKNOWLEDGMENTS contributed to manuscript revision. AE and IF are the responsible for the overall content as guarantors. All authors contributed to We wish to thank Christine O’Hara for help with the English the article and approved the submitted version. version of the manuscript. SUPPLEMENTARY MATERIAL FUNDING The Supplementary Material for this article can be found AGu has received funding from the Spanish Ministry of Science, online at: https://www.frontiersin.org/articles/10.3389/fcvm. Innovation and Universities (IJC2018- 037349-I). 2022.852954/full#supplementary-material REFERENCES and normal and low flow aortic stenosis. Circ Cardiovasc Imaging. (2013) 6:1009–17. doi: 10.1161/CIRCIMAGING.113.000515 1. Osnabrugge RLJ, Mylotte D, Head SJ, Van Mieghem NM, Nkomo VT, LeReun 13. Clavel M-A, Messika-Zeitoun D, Pibarot P, Aggarwal SR, Malouf J, Araoz CM, et al. Aortic stenosis in the elderly. J Am Coll Cardiol. (2013) 62:1002–12. PA, et al. The complex nature of discordant severe calcified aortic valve doi: 10.1016/j.jacc.2013.05.015 disease grading: new insights from combined Doppler echocardiographic 2. Hachicha Z, Dumesnil JG, Bogaty P, Pibarot P. Paradoxical low-flow, low- and computed tomographic study. J Am Coll Cardiol. (2013) 62:2329–38. gradient severe aortic stenosis despite preserved ejection fraction is associated doi: 10.1016/j.jacc.2013.08.1621 with higher afterload and reduced survival. Circulation. (2007) 115:2856–64. 14. González Gómez A, Fernández-Golfín C, Monteagudo JM, Izurieta C, doi: 10.1161/CIRCULATIONAHA.106.668681 Hinojar R, García A, et al. Severe aortic stenosis patients with preserved 3. Lancellotti P, Magne J, Donal E, Davin L, O’Connor K, Rosca M, et al. ejection fraction according to flow and gradient classification: prevalence Clinical outcome in asymptomatic severe aortic stenosis: Insights from the and outcomes. Int J Cardiol. (2017) 248:211–5. doi: 10.1016/j.ijcard.2017. new proposed aortic stenosis grading classification. J Am Coll Cardiol. (2012) 06.064 59:235–43. doi: 10.1016/j.jacc.2011.08.072 15. Parikh R, Goodman AL, Barr T, Sabik JF, Svensson LG, Rodriguez 4. Eleid MF, Sorajja P, Michelena HI, Malouf JF, Scott CG, Pellikka LL, et al. Outcomes of surgical aortic valve replacement for severe PA. Flow-gradient patterns in severe aortic stenosis with preserved aortic stenosis: Incorporation of left ventricular systolic function and ejection fraction: Clinical characteristics and predictors of survival. stroke volume index. J Thorac Cardiovasc Surg. (2015) 149:1558–66e1. Circulation. (2013) 128:1781–9. doi: 10.1161/CIRCULATIONAHA.113.0 doi: 10.1016/j.jtcvs.2015.03.008 03695 16. Kavianipour M, Farkhooy A, Flachskampf FA. Clinical outcome and 5. Tribouilloy C, Rusinaru D, Marchaux S, Castel AL, Debry N, Maizel J, et al. functional characteristics of patients with asymptomatic low-flow Low-gradient, low-flow severe aortic stenosis with preserved left ventricular low-gradient severe aortic stenosis with preserved ejection fraction ejection fraction: Characteristics, outcome, and implications for surgery. J Am are closer to high-gradient severe than to moderate aortic stenosis. Coll Cardiol. (2015) 65:55–66. doi: 10.1016/j.jacc.2014.09.080 Int J Cardiovasc Imaging. (2017) 34:545–52. doi: 10.1007/s10554-017- 6. Jander N, Minners J, Holme I, Gerdts E, Boman K, Brudi P, 1264-2 et al. Outcome of patients with low-gradient severe aortic stenosis 17. van Gils L, Clavel M-A, Vollema EM, Hahn RT, Spitzer E, Delgado V, and preserved ejection fraction. Circulation. (2011) 123:887–95. et al. Prognostic implications of moderate aortic stenosis in patients with doi: 10.1161/CIRCULATIONAHA.110.983510 left ventricular systolic dysfunction. J Am Coll Cardiol. (2017) 69:2383–92. 7. Maes F, Boulif J, Piérard S, De Meester C, Melchior J, Gerber B, doi: 10.1016/j.jacc.2017.03.023 et al. Natural history of paradoxical low-gradient severe aortic stenosis. 18. Strange G, Stewart S, Celermajer D, Prior D, Scalia GM, Marwick Circ Cardiovasc Imag. (2014) 7:714–22. doi: 10.1161/CIRCIMAGING.113. T, et al. Poor long-term survival in patients with moderate aortic 001695 stenosis. J Am Coll Cardiol. (2019) 74:1851–63. doi: 10.1016/j.jacc.2019. 8. Rezzoug N, Vaes B, Pasquet A, Gerber B, de Meester C, Van Pottelbergh 08.004 G, et al. Prevalence and prognostic impact of valve area—gradient 19. Saeed S, Vamvakidou A, Seifert R, Khattar R, Li W, Senior R. The patterns in patients ≥80 years with moderate-to-severe aortic stenosis impact of aortic valve replacement on survival in patients with normal (from the prospective BELFRAIL study). Am J Cardiol. (2015) 116:925–32. flow low gradient severe aortic stenosis: a propensity-matched comparison. doi: 10.1016/j.amjcard.2015.05.062 Eur Heart J Cardiovasc Imaging. (2019) 20:1094–101. doi: 10.1093/ehjci/ 9. Baumgartner H, Falk V, Bax JJ, De Bonis M, Hamm C, Holm PJ, jez191 et al. 2017 ESC/EACTS Guidelines for the management of valvular 20. Zheng Q, Djohan AH, Lim E, Ding ZP, Ling LH, Chan ES, et al. Effects heart disease. Eur Heart J. (2017) 38:2739–91. doi: 10.1016/j.rec.2017. of aortic valve replacement on severe aortic stenosis and preserved systolic 12.013 function: systematic review and network meta-analysis. Sci Rep. (2017) 7:1–9. 10. Baumgartner H, Hung J, Bermejo J, Chambers JB, Edvardsen T, Goldstein doi: 10.1038/s41598-017-05021-9 S, et al. Recommendations on the echocardiographic assessment of 21. Otto CM, Nishimura RA, Bonow RO, Carabello BA, III JPE, Gentile F, et al. aortic valve stenosis: a focused update from the european association of 2020 ACC/AHA guideline for the management of patients with valvular heart cardiovascular imaging and the american society of echocardiography. disease: a report of the American College of Cardiology/American Heart J Am Soc Echocardiogr. (2017) 30:372–92. doi: 10.1016/j.echo.2017. Association joint committee on clinical practice guidelines. Circulation. (2021) 02.009 143:E72–227. doi: 10.1161/CIR.0000000000000923 11. Clavel M-A, Dumesnil JG, Capoulade R, Mathieu P, Sénéchal M, Pibarot P. 22. Dahl JS, Eleid MF, Michelena HI, Scott CG, Suri RM, Schaff H V, et al. Outcome of patients with aortic stenosis, small valve area, and low-flow, low- Effect of left ventricular ejection fraction on postoperative outcome in gradient despite preserved left ventricular ejection fraction. J Am Coll Cardiol. patients with severe aortic stenosis undergoing aortic valve replacement. (2012) 60:1259–67. doi: 10.1016/j.jacc.2011.12.054 Circ Cardiovasc Imaging. (2015) 8:1–8. doi: 10.1161/CIRCIMAGING.114. 12. Barone-Rochette G, Piérard S, Seldrum S, de Meester de. Ravenstein C, 002917 Melchior J, Maes F, et al. Aortic valve area, stroke volume, left ventricular 23. Capoulade R, Le Ven F, Clavel M-A, Dumesnil JG, Dahou A, Thébault C, hypertrophy, remodeling, and fibrosis in aortic stenosis assessed by cardiac et al. Echocardiographic predictors of outcomes in adults with aortic stenosis. magnetic resonance imaging: comparison between high and low gradient Heart. (2016) 102:934–42. doi: 10.1136/heartjnl-2015-308742 Frontiers in Cardiovascular Medicine | www.frontiersin.org 9 April 2022 | Volume 9 | Article 852954 Galian-Gay et al. Low-Flow Low-Gradient Aortic Stenosis Prognosis 24. Ito S, Miranda WR, Nkomo VT, Connolly HM, Pislaru S V, Greason Conflict of Interest: The authors declare that the research was conducted in the KL, et al. Reduced left ventricular ejection fraction in patients with aortic absence of any commercial or financial relationships that could be construed as a stenosis. J Am Coll Cardiol. (2018) 71:1313–21. doi: 10.1016/j.jacc.2018. potential conflict of interest. 01.045 25. Chin CWL, Everett RJ, Kwiecinski J, Vesey AT, Yeung E, Esson G, Publisher’s Note: All claims expressed in this article are solely those of the authors et al. Myocardial fibrosis and cardiac decompensation in aortic stenosis. and do not necessarily represent those of their affiliated organizations, or those of JACC Cardiovasc Imaging. (2017) 10:1320–33. doi: 10.1016/j.jcmg.2016. the publisher, the editors and the reviewers. Any product that may be evaluated in 10.007 this article, or claim that may be made by its manufacturer, is not guaranteed or 26. Galli E, Lancellotti P, Sengupta PP, Donal E. LV mechanics in mitral and endorsed by the publisher. aortic valve diseases :value of functional assessment beyond ejection fraction. JACC: Cardiovasc Imaging. (2014) 7:151–66. doi: 10.1016/j.jcmg.2014. 07.015 Copyright © 2022 Galian-Gay, Escalona Silva, Teixidó-Turà, Casas, Ferrer-Sistach, 27. Ng ACT, Prihadi EA, Antoni ML, Bertini M, Ewe SH, Ajmone Marsan N, et al. Mitroi, Mingo, Monivas, Saura, Vidal, Trasca, Moral, Calvo, Castiñeira Busto, Left ventricular global longitudinal strain is predictive of all-cause mortality Sánchez, Gonzalez, Guzman, Mora, Arnau Vives, Peteiro, Bouzas, Mas-Stachurska, independent of aortic stenosis severity and ejection fraction. Eur Hear J - González-Alujas, Gutiérrez, Fernandez-Galera, Valente, Guala, Ruiz-Muñoz, Avilés, Cardiovasc Imaging. (2018) 19:859–67. doi: 10.1093/ehjci/jex189 Palomares, Ferreira and Evangelista. This is an open-access article distributed 28. Magne J, Cosyns B, Popescu BA, Carstensen HG, Dahl J, Desai MY, under the terms of the Creative Commons Attribution License (CC BY). The use, et al. Distribution and prognostic significance of left ventricular global distribution or reproduction in other forums is permitted, provided the original longitudinal strain in asymptomatic significant aortic stenosis an individual author(s) and the copyright owner(s) are credited and that the original publication participant data meta-analysis. JACC: Cardiovasc Imag. (2019) 12:84–92. in this journal is cited, in accordance with accepted academic practice. No use, doi: 10.1016/j.jcmg.2018.11.005 distribution or reproduction is permitted which does not comply with these terms. Frontiers in Cardiovascular Medicine | www.frontiersin.org 10 April 2022 | Volume 9 | Article 852954