Carter‐Storch, Rasmus

BACKGROUND Patients with severe aortic stenosis (AS) exhibit heterogeneous flow-gradient hemodynamics and ventricular remodeling, which may influence symptomatic, functional, and structural responses to transcatheter aortic valve implantation (TAVI). Thus, we evaluated differences in functional recovery and reverse remodeling after transfemoral TAVI across flow-gradient phenotypes. METHODS In this sub-study of the COMPARE-TAVI 1 trial, 975 patients undergoing transfemoral TAVI were classified as classical low-flow low-gradient (cLFLG, 9.1%), paradoxical low-flow low-gradient (pLFLG, 7.7%), low-flow high-gradient (24.7%), normal-flow low-gradient (NFLG, 13.0%), and normal-flow high-gradient (45.4%). The primary functional outcome was longitudinal change in six-minute walk test distance (6MWTD) from baseline to 1 year follow-up. Secondary endpoints included changes in NYHA functional class and reverse remodeling from baseline to 1 year follow-up along with the incidence and risk of all-cause death and a composite MACE-endpoint. RESULTS Mean 6MWTD increased by 59±4 meters at 1-month (p=0.000) with no additional improvement at 1-year, but with heterogeneity between groups (p=0.000). Improvements among NFLG, cLFLG and low-flow high-gradient AS were comparable with normal-flow high-gradient AS, while pLFLG AS exhibited significantly increments at 1-year (−28±15 meters, p=0.007). Patients with NFLG, cLFLG and pLFLG were more symptomatic at baseline (NYHA ≥III: 40.5%, 57.3% and 50.6%, respectively, p=0.000). NYHA improved in all groups at 1-year follow-up (p=0.000), although persistent symptoms at 1-year were most frequent in pLFLG (NYHA ≥II; 38.7%, p=0.012). Reverse remodeling was also comparable between normal-flow high-gradient AS and NFLG, cLFLG, and low-flow high-gradient AS, respectively, but attenuated in pLFLG AS in both unadjusted and adjusted analyses. No differences were observed in the incidence and risk of all-cause death or the composite MACE-endpoint. CONCLUSION TAVI associates with functional recovery across all flow-gradient phenotypes, although with heterogeneous responses. Patients with NFLG showed comparable functional recovery and reverse remodeling at 1-year follow-up compared with normal-flow high-gradient AS, whereas pLFLG demonstrated attenuated benefits across all parameters.

Background The hemodynamic profile and remodeling patterns of paradoxical low‐flow, low‐gradient aortic stenosis are well understood. However, some patients with severe aortic stenosis exhibit eccentric remodeling with enlarged left ventricular cavities, enabling a normal flow, low ejection fraction ( NF ‐ LEF ) phenotype. We assessed the prevalence, hemodynamic characteristics, and post‐transcatheter aortic valve implantation outcomes of NF ‐ LEF . Methods In this substudy of the COMPARE‐TAVI 1 trial, 979 patients undergoing transfemoral transcatheter aortic valve implantation were stratified by left ventricular ejection fraction (LVEF) (< or ≥50%) and stroke volume index (< or ≥35 mL/m 2 ) into 4 groups: normal flow, normal LVEF, NF‐LEF, low flow, normal ejection fraction, and low flow, low ejection fraction. Results NF‐LEF was observed in 10.7% of patients. Reduced LVEF was associated with previous myocardial infarction, pacemakers, New York Heart Association class >2, atrial fibrillation, moderate or worse mitral regurgitation, and larger left ventricular cavities ( P <0.001) with eccentric hypertrophy ( P =0.004). Compared with low‐flow, low‐ejection fraction, patients with NF‐LEF more frequently had moderate or worse aortic regurgitation ( P =0.007), whereas low flow, low ejection fraction showed poorer diastolic indices, suggesting diastolic dysfunction with high left ventricular filling pressures. Patients with low flow, normal ejection fraction were the most symptomatic and showed less improvement in 6‐minute walk distance at 1 year compared with normal flow, normal ejection fraction. During follow‐up, both low‐flow groups demonstrated significant increases in stroke volume index ( P <0.001), whereas LVEF also improved among patients with reduced LVEF ( P <0.001). Conclusions NF‐LEF is a prevalent aortic stenosis phenotype characterized by preserved flow despite reduced LVEF, likely driven by eccentric remodeling with moderate or worse aortic regurgitation and more favorable diastolic properties, with similar survival and time‐to‐event outcomes across phenotypes after transcatheter aortic valve implantation at long‐term follow‐up. Despite higher comorbidity burdens, patients with NF‐LEF showed functional and clinical improvements comparable with normal flow, normal ejection fraction, indicating a severe aortic stenosis phenotype.

Abstract Aims This study aims to investigate the prognostic role of Stage 3 and 4 cardiac damage (CD) after transcatheter aortic valve intervention (TAVI), dependent on whether comorbidities contributing to right heart dysfunction were present. Methods and results Patients with severe aortic stenosis (AS) undergoing TAVI were included. Patients were divided into three groups: Stage 0–2 CD; Stage 3–4 CD, isolated AS (Stage 3–4 CD without significant concomitant chronic obstructive pulmonary disease, mitral annular calcification, mitral stenosis, mitral regurgitation, previous coronary artery bypass graft surgery, or cardiac amyloidosis); Stage 3–4 CD, AS with comorbidities (Stage 3–4 CD with ≥ 1 of these comorbidities). Futility was defined as death or Stage 3–4 New York Heart Association class dyspnoea 1 year after TAVI. Of 985 included patients, 822 (83%) had Stage 1–2 CD; 101 (10%) had Stage 3–4 CD, isolated AS; and 62 (6%) had Stage 3–4 CD, AS with comorbidities. Futility was not more common in Stage 3–4 CD groups (Stage 1–2 CD, 10%; Stage 3–4 CD, isolated AS, 17%; Stage 3–4 CD, AS with comorbidities, 15%, P = 0.09). Baseline and 1-year NYHA class were higher in Stage 3–4 CD compared with Stage 1–2 CD (P &lt; 0.01). The 6 min walking test distance increased similarly in all groups at 1 year. Conclusion Potential comorbidities contributing to right heart dysfunction were common among patients in Stage 3–4 CD undergoing TAVI. Stage 3–4 CD was not associated with a significantly higher risk of futility, irrespective of comorbidities, and they experienced a similar functional improvement after TAVI.

Abstract Aims Aortic valve-sparing root replacement is recommended over composite root replacement for aortic root aneurysms, especially in younger patients, but long-term outcomes in low-volume nationwide settings remain unclear. The objectives are to compare long-term survival, stroke, and reoperation rates between the two procedures in a low-volume national setting. Methods and results Patients were identified from the Western Danish Heart Registry and the Danish Heart Registry. Cases were validated by review of operative descriptions. The primary outcome was long-term survival from all-cause mortality; secondary outcomes included stroke, reoperation, recurrent aortic regurgitation, and aortic stenosis. Groups were balanced using propensity score matching. Echocardiographic data were provided for the matched cohort. We identified 760 patients treated with composite root replacement and 179 patients with aortic valve-sparing root replacement between January 2010 and April 2022. Mean follow-up was 6.5 years. Composite root replacement patients were younger [50.7 years (SD 14.1) vs. 55.2 (SD 13.5), P &lt; 0.001], but more comorbid with a median EuroSCOREII of 5.5 [interquartile range (IQR): 3.3–11.7] vs. 3.4 (IQR: 2.6–5.0) (P &lt; 0.001). After matching 157 patients per group, aortic valve-sparing root replacement showed improved 10-year survival [91.2%, 95% confidence interval (CI) 82.3–95.8 vs. 80.4%, 95% CI 70.0–87.5, log-rank P = 0.026], with lower 10-year stroke risk (4.9%, 95% CI 1.8–13.0 vs. 18.9%, 95% CI 11.7–29.9, log-rank P = 0.007). Risk of reoperation was nonsignificant (log-rank P = 0.12), which was consistent in the crude population when accounting for competing risk of death (log-rank P = 0.09). Conclusion In this nationwide study, aortic valve-sparing root replacement was associated with better long-term survival and lower stroke risk, supporting its role as a durable surgical option for selected patients.

Abstract Aims In aortic stenosis (AS), estimation of left ventricular (LV) contractility is difficult as most markers of systolic LV function are load-dependent. The ratio of LV ejection fraction (LVEF) to end-systolic wall stress (ESWS), has been widely accepted as a marker of contractility. However, no studies have evaluated if this ratio is affected by loading conditions. The study describes changes in ESWS and ESWS corrected LVEF after transcatheter aortic valve replacement (TAVR). Methods and results In this prospective study, 41 patients with severe AS underwent echocardiography, LV catheterisation, and computed tomography (CT) before and immediately after TAVR. ESWS was estimated from echocardiography alone (ESWSEcho), combining CT LV dimensions and echocardiographic gradients (ESWSCT + echo) and combining CT LV dimensions and invasively measured LV end-systolic pressure (ESWSCT + Invasive). ESWSecho, ESWSCT + echo and ESWSCT + Invasive all decreased significantly after TAVR (89 ± 48 vs. 57 ± 37 Kdynes/cm2, P &lt; 0.01; 69 ± 8 vs. 51 ± 8 Kdynes/cm2, P &lt; 0.01, and 197 ± 69 vs. 137 ± 48 Kpa/cm2, P &lt; 0.01, respectively). We observed weak to moderate associations between the methods. After TAVR, LVEF corrected to ESWSecho, ESWSCT + echo and ESWSCT + Invasive increased (0.93 ± 0.07 vs. 1.91 ± 2.1, P = 0.013; 0.36 ± 0.19 vs. 0.58 ± 0.33, P &lt; 0.01, and 0.3 ± 0.02 vs. 2.5 ± 1.5, P &lt; 0.01, respectively). Conclusion ESWSecho, ESWSCT + echo and ESWSCT + Invasive decreased significantly after TAVR suggesting they reflect afterload, but independent of method, ESWS corrected LVEF increased slightly post-TAVR, indicating load dependency.

Abstract Background Dobutamine stress echocardiography (DSE) is recommended to distinguish between true-severe and pseudo-severe aortic stenosis (AS) in patients with low flow low-gradients and left ventricular ejection fraction (LVEF) &lt;50%. However, DSE has mostly been tested in the setting of LVEF&lt;35%. Purpose The purpose of this study was to examine the diagnostic accuracy of DSE according to aortic valve calcification (AVC) score, in patents with low-flow, low-gradient AS across a wide range of LVEF. Methods Patients with aortic mean gradient &lt;40 mmHg, aortic valve area (AVA) &lt;1.0 cm2, and stroke volume index (SVi) ≤35 mL/m2 undergoing DSE were identified from three prospectively collected patient cohorts, and stratified according to LVEF; &lt;35%, 35-50% and &gt;50%. Severe AS was defined as AVC score ≥2000 AU among men, and ≥1200 AU for women. Recommendation for severe AS according to DSE, are an AVA &lt;1.0 cm2 combined with an aortic mean gradient ≥40 mmHg or peak velocity ≥4 m/s. Receiver operating characteristic curves for DSE-derived AVA, mean gradient and Vmax were used to identify optimal cut-off points for each LVEF subgroup. Results Of the 221 patients included in the study, 78 (35%) presented with LVEF &lt;35%, 67 (30%) with LVEF 35-50%, and 76 (34%) with LVEF &gt;50%. Baseline characteristics are presented in the table. Based on AVC, severe AS was present in 102 (46%) of patients. Using recommended thresholds for severe AS for AVC and DSE, led to a sensitivity of 49%, a specificity of 84% and an accuracy of 67% for DSE for all patients with LVEF &lt;50%, but with significant heterogeneity between groups figure. AVA performed rather uniformly across LVEF subgroups; (AUC =0.68 vs 0.62 vs 0.54, p=0.36) LVEF&lt;35%, LVEF 35-50%, LVEF&gt;50% respectively and displayed a rather uniform optimal cut-off (1.0 cm2 vs 0.9 cm2 vs 0.8 cm2). However, mean gradient and Vmax during DSE, both showed significantly diagnostic heterogeneity across LVEF groups (AUC= 0.90 vs 0.67 vs 0.65, p=&lt;0.001 and AUC= 0.90 vs 0.66 vs 0.60, p=&lt;0.001) with different optimal thresholds (30 mmHg & 3.8 m/s, 45 mmHg & 4.3 m/s and 37mmHg & 4 m/s, LVEF&lt;35%, LVEF 35-50%, LVEF&gt;50%, respectively). Conclusion Our study shows, that the association between DSE gradients and AS severity assessed by AVC demonstrates important heterogeneity depending on LVEF. While DSE had the highest accuracy in patients with LVEF&lt;35% both patients with LVEF 35-50%, and patients with LVEF&gt;50% showed significantly less concordance between DSE and AVC.

Background Haemodynamic exercise testing is important for evaluating patients with dyspnoea on exertion and preserved ejection fraction. Despite very different pathologies, patients with pressure (aortic stenosis (AS)) and volume (mitral regurgitation (MR)) overload and diastolic dysfunction after recent acute myocardial infarction (AMI) reach similar filling pressure levels with exercise. The pressure–flow relationships (the association between change in cardiac output (∆CO) and change in pulmonary arterial wedge pressure (∆PAWP) may provide insight into haemodynamic adaptation to exercise in these groups. Methods and results One hundred sixty-eight subjects aged >50 years with a left ventricular ejection fraction of ≥50% underwent invasive exercise testing. They were enrolled in four different studies: AS (40 patients), AMI (52 patients), MR (43 patients) and 33 healthy subjects. Haemodynamic data were measured at rest, at 25 W, 75 W and at peak exercise. In all groups, PAWP increased with exercise. The greatest increase was observed in patients with AMI (from 12.7±3.9 mm Hg to 33.1±8.2 mm Hg, p<0.0001) and patients with AS (from 11.8±3.9 mm Hg to 31.4±6.1 mm Hg, p<0.0001), and the smallest was observed in healthy subjects (from 8.3±2.4 mm Hg to 21.1±7.5 mm Hg, p<0.0001). In all groups, the relative pressure increase was greatest at the beginning of the exercise. CO increased most in healthy patients (from 5.3±1.1 to 16.0±3.0 L/min, p<0.0001) and least in patients with AS (from 5.3±1.2 L/min to 12.4±2.6 L/min, p<0.0001). The pressure–flow relationships (∆PAWP/∆CO) and differed among groups (p = 0.02). In all groups, the pressure–flow relationship was steepest in the initial phase of the exercise test. The AMI and AS groups (2.3±1.2 mm Hg/L/min and 3.0±1.3 mm Hg/L/min, AMI and AS, respectively) had the largest overall pressure–flow relationship; the healthy group had the smallest initially and at peak exercise (1.3±1.1 mm Hg/L/min) followed by MR group (1.9±1.4 mm Hg/L/min). Conclusion The pressure–flow relationship was steepest in the initial phase of the exercise test in all groups. The pressure–flow relationship differs between groups. Trial registration numbers NCT01974557 , NCT01046838 , NCT02961647 and NCT02395107 .

AbstractAimsNew diastolic dysfunction (DD) guidelines were introduced in 2016 to replace the 2009 guidelines, but have not yet been evaluated in aortic stenosis (AS). We aimed to compare the 2009 and 2016 DD guidelines in severe AS patients in terms of association with left ventricular (LV) and left atrial (LA) remodeling, with pulmonary capillary wedge pressure (PCWP) at rest and exercise, and with prognosis.Methods and resultsWe included 212 patients with severe AS (112 undergoing AVR, 100 asymptomatic). Echocardiography, magnetic resonance imaging, and brain natriuretic peptides (BNP) were performed/measured. Thirty‐nine asymptomatic patients had PCWP measured during rest and maximal exertion. Asymptomatic patients were followed for 3.1 years for the combined endpoint of death, AVR or admission with heart failure. The 2009 and 2016 DD guidelines agreed poorly with each other (Cohens’ κ = .15). 2009 guidelines showed many ambiguous DD findings. With the 2016 guidelines, 20% of patients had indeterminate DD. DD grade 2 according to 2016 guidelines showed stronger association with symptom status, BNP, global longitudinal strain (GLS) and peak exercise PCWP than 2009 guidelines. For indeterminate DD patients according to 2009 guidelines, GLS above the median was associated with event‐free survival (HR .11 (95% CI .02–.53)). For neither guideline was DD associated with the combined endpoint in asymptomatic patients.ConclusionThe 2016 guidelines show a stronger association with BNP, GLS, and exercise PCWP than the 2009 guidelines. The 2016 guidelines result in 20% of patients with indeterminate DD; however, these patients may possibly be stratified according to GLS.

Background First-phase ejection fraction (EF1), the left ventricular (LV) ejection fraction (EF) until the time of peak transaortic velocity, is a novel marker of subclinical LV dysfunction able to predict adverse events in aortic stenosis (AS). This study investigated the association between end-systolic wall stress (ESWS) and EF1 in severe AS, as well as the prognostic value of EF1 in severe asymptomatic AS. Methods Two prospectively gathered cohorts of 94 asymptomatic patients and 108 symptomatic patients scheduled for aortic valve replacement (AVR), all with severe AS (aortic valve area <1 cm2) were stratified according to the median value of EF1 (33%). EF1 was defined as the EF at peak transaortic velocity. Asymptomatic patients were followed up for 3 years for the combined end-point of death, AVR or admission with heart failure. Results EF1 correlated with EF and was inversely associated with ESWS. In multivariate regression analysis, ESWS (p<0.001) and replacement fibrosis measured by MRI (p=0.02) were associated with EF1. Among asymptomatic patients, EF1 above the median was associated with the combined primary endpoint (HR=0.53 (95% CI 0.33 to 0.87)), while global longitudinal strain and EF were not. Among 42 patients with discordant AS (mean gradient <40 mm Hg), EF1 above median was associated with the primary endpoint (HR 0.28 (95% CI 0.12 to 0.61)). Conclusion EF1 is an afterload-dependent measure that is associated with events in patients with asymptomatic severe AS. The afterload dependency of EF1 may be useful in timing of risk stratification in patients with discordant AS. Trial registration numbers NCT02395107 and NCT02316587.

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Danish Heart Association. Background First-phase ejection fraction (EF1), the ejection fraction (EF) until the time of peak systolic flow may be a sensitive marker of subclinical left ventricular (LV) dysfunction. This study investigated the prognostic value of EF1 in asymptomatic and symptomatic severe aortic stenosis (AS). Methods This study included 94 asymptomatic and 108 symptomatic patients with severe AS. The prognostic value of EF1 was compared with other echocardiographic markers and magnetic resonance imaging (MRI) measured end-systolic wall stress and late gadolinium enhancement fibrosis (LGE). Asymptomatic patients were followed up for 3.0 years (primary outcome death or aortic valve replacement). Symptomatic patients were followed up for 4.3 years (primary outcome death). Results In multivariate regression analysis wall stress (p &lt; 0.001) and LGE (p = 0.03) were associated with EF1. In the asymptomatic cohort EF1 was significantly associated with the end-point, especially among the subgroup of patients with a mean gradient &lt; 40 mmHg (HR 0.91, p = 0.005), while global longitudinal strain was not. In the surgical cohort, EF1 was borderline associated with death (p = 0.08) which was significant after correction for LGE (HR 0.90, p = 0.02). Conclusion EF1 is a predictor of death or AVR in asymptomatic AS, especially among discordantly graded patients with low area and low gradient. Univariate β (95% CI) p-value Multivariate β (95% CI) p-value Age (years) .03 (-.09 to .16) 0.58 .03 (-.12 to .18) 0.69 Sex (male) -.12 (-2.26 to 2.03) 0.91 .24 (-2.31 to 2.80) 0.85 Hypertension -.08 (-2.22 to 2.07) 0.95 Aortic valve area (0.01 cm2) .09 (.04 to .14) 0.001 Aortic mean gradient (mmHg) -.02 (-.08 to .04) 0.56 LV end-diastolic volume (ml) -.07 (-.11 to -.03) &lt;0.001 LV end-systolic volume (ml) -.17 (-.22 to -.12) &lt;0.001 -.07 (-.15 to .02) 0.11 LV ejection fraction (%) .28 (.19 to .38) &lt;0.001 LV peak ejection time (ms) -.07 (-.16 to .02) 0.13 LGE fibrosis -3.04 (-5.67 to -.42) 0.02 -2.64 (-4.99 to -.30) 0.03 Wall stress (kdynes/m3) -.10 (-.13 to -.08) &lt;0.001 -.08 (-.12 to -.04) &lt;0.001 Multivariate linear regression analysis for associations with first phase ejection fraction. LV is left ventricular, LGE late gadolinium enhancement Abstract Figure. AVR-free survival according to EF1