Low-flow Low-gradient Aortic Stenosis Research Articles

Prevalence and Prognostic Significance of Right Ventricular Dysfunction in Patients With Severe Low-Flow, Low-Gradient Aortic Stenosis Undergoing Transcatheter Aortic Valve Replacement.

Whether the presence of right ventricular (RV) dysfunction may influence the clinical outcome of patients with low-flow, low-gradient aortic stenosis (LFLG-AS) undergoing transcatheter aortic valve replacement (TAVR) has not yet been established. This study included consecutive patients with LFLG-AS undergoing TAVR at 2 high-volume Italian centers. RV dysfunction before TAVR procedure was defined as tricuspid annular plane systolic excursion assessed by transthoracic echocardiography lower than <17 mm. The primary outcome was all-cause death at 1 year. The propensity score weighting technique was implemented to account for potential selection bias between patients with and without RV dysfunction. A prespecified subgroup analysis was conducted to evaluate the consistency of the results in patients with classical and paradoxical LFLG-AS forms. This study included 392 patients; of them, 97 (24.7%) patients showed RV dysfunction before TAVR. At propensity score-weighted adjusted Cox regression analysis, RV dysfunction, according to dichotomous definition, was associated with an increased risk for the primary outcome (adjusted hazard ratio [HR], 3.11 [95% CI, 1.58-6.13]), cardiovascular death (adjusted HR, 3.26 [95% CI, 1.58-6.72]), and major adverse cardiovascular and cerebrovascular events (adjusted HR, 3.39 [95% CI, 1.76-6.53]). Conversely, no difference was detected for the risk of stroke and of permanent pacemaker implantation. No significant interaction of the classical and paradoxical LFLG-AS subgroups was detected for all the outcomes of interest. This study suggests that RV dysfunction echocardiographically assessed by tricuspid annular plane systolic excursion may improve the prognostic stratification of patients with LFLG-AS undergoing TAVR.

Myocardial SGLT2 expression and cardiac remodeling in patients with severe aortic stenosis: the BIO-AS Study

Abstract Background Cardiac remodeling plays a major role in the prognosis of patients with aortic stenosis (AS) and could impact the benefits of aortic valve replacement. Blood and tissue biomarkers have a differential pattern and expression level in patients with AS, which may retain a pathophysiological role in cardiac remodeling and metabolism. However, the data available are limited and contradictory. Aim Our study aimed to evaluate the expression of sodium-glucose cotransporter 2 (SGLT2) gene and protein in patients with severe AS stratified in high gradient (HG) and low flow-low gradient (LF-LG) AS and its association with cardiac functional impairments. Methods Gene expression and protein levels of main biomarkers of cardiac fibrosis (Galectin-3, sST2, Serpin-4, PINP, PICP, Collagen, TGF-b), inflammation (GDF-15, IL-6, NF-kB), oxidative stress (SOD1, SOD2), and cardiac metabolism (NHE, PPAR-a, PPAR-g, GLUT1, and GLUT4) were evaluated in blood samples and heart biopsies of 45 patients with AS. Results Our study showed SGLT2 gene and protein hyper-expression in patients with LF-LG AS, compared to controls and HG AS (p&amp;lt;0.05). These differences remained significant even after adjusting for age, gender, body mass index, history of diabetes mellitus, arterial hypertension, and coronary artery disease. SGLT2 gene expression was positively correlated with: i) TGF-b (r=0.72, p&amp;lt;0.001) and collagen (r=0.73, p&amp;lt;0.001) as markers of fibrosis; ii) NF-kB (r=0.36, p&amp;lt;0.01) and myocardial IL-6 (r=0.68, p&amp;lt;0.001) as markers of inflammation: iii) SOD2 (r=-0.38, p&amp;lt;0.006) as a marker of oxidative stress; iv) GLUT4 (r= 0.33, p&amp;lt;0.02) and PPAR-a (r=0.36, p&amp;lt;0.01) as markers of cardiac metabolism (Figure 1). Conclusion In patients with LF-LG AS, SGLT2 gene and protein were hyper-expressed in cardiomyocytes and associated with myocardial fibrosis, inflammation, and oxidative stress. The hyper-expression of the SGLT2 gene and protein in patients with LF-LG might pave the way for using SGLT2-Is in this subset population, with the potential to improve the outcomes of AVR and reduce the likelihood of re-hospitalization within one year.Figure 1

Long-term outcomes of aortic stenosis patients with different flow/gradient patterns undergoing transcatheter aortic valve implantation

Abstract Background Few data exist on the comparative long-term outcomes of severe aortic stenosis (AS) patients with different flow-gradient patterns undergoing transcatheter aortic valve implantation (TAVI). This study sought to evaluate the impact of the pre-TAVI flow-gradient pattern on long-term clinical outcomes after TAVI. Methods Consecutive patients with severe AS undergoing TAVI in our institution were screened and prospectively enrolled. Patients were divided into four subgroups according to pre-TAVI flow/gradient pattern: (i) low flow—low gradient (LF-LG): stroke volume indexed (SVi) ≤ 35 mL/m2 and mean gradient (MG) &amp;lt; 40 mmHg); (ii) normal flow—low gradient (NF-LG): SVi &amp;gt; 35 mL/m2 and MG &amp;lt; 40 mmHg; (iii) low flow—high gradient (LF-HG): Svi 35 mL/m2 and MG ≥ 40 mmHg and (iv) normal flow—high gradient (NF-HG): SVi &amp;gt; 35 mL/m2 and MG ≥ 40 mmHg. Clinical follow-up was obtained at 12 months, and yearly thereafter until 5-year follow-up was complete for all patients. Results A total of 272 patients with complete echocardiographic and clinical follow-up were included in our analysis. Their mean age was 80 ± 7 years and the majority of patients (N = 138, 50.8%) were women. 62 patients (22.8% of the study population) were distributed in the LF-LG group, 98 patients (36%) were LF-HG patients, 95 patients (34.9%) were NF-HG, and 17 patients (6.3%) were NF-LG. There was a greater prevalence of comorbidities among LF-LG AS patients. One-year all-cause mortality differed significantly between the four subgroups of AS patients (log-rank p: 0.022) and was more prevalent among LF-LG patients (25.8%) compared to LF-HG (11.3%), NF-HG (6.3%) and NF-LG patients (18.8%). At 5-year follow-up, global mortality remained persistently higher among LF-LG patients (64.5%) compared to LF-HG (47.9%), NF-HG (42.9%), and NF-LG patients (58.8%) (log-rank p: 0.029) (Figure 1). At multivariable Cox hazard regression analysis, baseline SVi (HR: 0.951, 95% C.I.; 0.918–0.984), the presence of at least moderate tricuspid regurgitation at baseline (HR: 3.091, 95% C.I: 1.645–5.809) and at least moderate paravalvular leak (PVL) post-TAVI (HR: 1.456, 95% C.I.: 1.106–1.792) were significant independent predictors of late global mortality. Conclusions Patients with LF-LG AS have acceptable 1-year outcomes, but exhibit exceedingly high 5-year mortality following TAVI. The presence of low transvalvular flow and at least moderate tricuspid regurgitation at baseline and significant paravalvular leak post-TAVI were associated with poorer long-term outcomes in the entire cohort of AS patients.

Postoperative assessment of interstitial myocardial fibrosis in aortic valve pathologies: insights from a cardiac magnetic resonance study

Abstract Background Data on the characteristics of diffuse myocardial fibrosis (DMF) among patient undergoing valve surgery for aortic regurgitation (AR), high-gradient aortic stenosis (HG-AS), and low-flow low-gradient aortic stenosis with low ejection fraction (LFLG-AS) are limited. Purpose To assess the postoperative characteristics of DMF and to compare post- and pre-operative cardiac magnetic resonance imaging (CMR) data. Methods Patients diagnosed with AR (38), HG-AS (62), and LFLG-AS (39), who met criteria for surgical intervention, were prospectively included. Pseudo-severe AS was excluded. Post-operative CMR was performed 6 to 8 months after surgery, and a comparison between post- and pre-operative data was made (delta=Δ). Quantitative analysis included assessment of extracellular volume fraction (ECV), indexed ECV (iECV), and myocardial mass (MM). Results There were differences in baseline characteristics among patients with AR, HG-AS, and LFLG-AS concerning age (54±14 vs 63±8 vs 67±8 years, respectively; p&amp;lt;0.01), male gender (75% vs 50% vs 82%, respectively; p&amp;lt;0.01), NYHA functional class III and IV (37.5% vs 55.2% vs 30.8%, respectively; p=0.03), EuroSCORE II (1.16±0.5 vs 1.26±0.46 vs 3.39±2.65%, respectively; p&amp;lt;0.01), and STS (0.74±0.29 vs 1.11±0.5 vs 3.21±2.11%, respectively; p&amp;lt;0.01). Global ECV was similar between groups (29.2±5.6 vs 27.0±3.6 vs 29.4±5.9%, respectively; p=0.01), MM was different between groups (215±76 vs 161±51 vs 203±51g, respectively; p&amp;lt;0.01), and iECV was different between groups and significantly higher in AS patients (50.1±31.0 vs 21±8 vs 34.2±10.2ml/m², respectively; p&amp;lt;0.01). All patients underwent valve surgery and there were differences regarding extracorporeal circulation time (94±25 vs 97±20 vs 75±41min, respectively; p&amp;lt;0.01), and 30-day mortality (0% vs 3% vs 15%, respectively; p&amp;lt;0.01). Post-surgery data from patients with AR (32), HG-AS (62), and LFLG-AS (21) demonstrated a comparable decrease across all groups concerning preoperative MM (ΔMM: -39.3±41.5 vs -33.4±30.9 vs -23.4±34.2g, respectively; p=0.36) (Figure 1). In contrast, iECV decreased post-surgery only in AR, remaining stable in HG-AS and LFLG-AS (ΔiECV: -19.1±22.5 vs -1.4±7.4 vs 0.9±12ml/m², respectively; p&amp;lt;0.01). Thus, postoperative ECV maintained commensurate values in AR, while increasing in HG-AS and LFLG-AS (ΔECV: -0.1±4.5 vs 1.5±5.1 vs 2.9±4.9%, respectively; p=0.09). Δ left ventricular ejection fraction (LVEF) was similar across groups (ΔLVEF: -1.5±10.6 vs 1.1±11.7 vs 2.6±16%, respectively; p=0.44). Conclusion In the postoperative period, a decrease in MM was observed in all groups of aortic valve pathologies. However, only patients with AR showed a simultaneous and proportional reduction in DMF mass, explaining the patterns of ECV variation. Thus, the reduction of DMF in the postoperative period appears to vary according to the phenotypes presented, and patients with AR exhibit early reverse remodeling despite having high levels of DMF.Delta iECV, LV mass and ECV measures

Prognostic Relevance of Gradient and Flow Status in Severe Aortic Stenosis.

Background: Severe aortic stenosis (AS) may present with different flow, gradient and left ventricular ejection fraction (LVEF) patterns. Paradoxical low-flow low-gradient (PLF-LG) severe AS has a specific clinical profile, but its prognosis and management remain controversial. Our aim is to evaluate the impact of different AS patterns in the incidence of major clinical events. Methods: A retrospective observational study was carried out on all the consecutive patients diagnosed with severe AS at our tertiary hospital centre in 2021. Echocardiographic measurements were carefully reviewed, and patients were classified following current guidelines into four categories: high gradient (HG), concordant low-flow low-gradient (CLF-LG), paradoxical low-flow low-gradient (PLF-LG) and normal-flow low-gradient (NF-LG). The baseline characteristics and clinical events (heart failure admission, intervention and death) at 1-year follow-up were collected from medical records. The association between categories and events was established using Student's t test or ANOVA as required. Results: 205 patients with severe AS were included in the study (81 ± 10 years old, 52.7% female). Category distribution was as follows: HG (138, 67.3%), PLF-LG (34, 19.8%), CLF-LG (21, 10.2%) and NF-LG (12, 5.9%). During the follow-up, 24.8% were admitted due to heart failure, 68.3% received valve replacement (51.7% TAVR) and 22% died. Severe tricuspid regurgitation was more frequent in patients with PLF-LG than in HG AS (14.7% vs. 2.2%; p < 0.01). Despite no differences in intervention rate, more patients with PLF-LG (32.4% vs. 15.9%; p = 0.049) died during the evolution. Conclusions: The PLF-LG pattern was the second most common pattern of severe AS in our cohort, and it was related to a higher mortality with no differences in intervention rate. Thus, this controversial category, rather than being underestimated, should be followed closely and considered for early intervention.

Cellular and extracellular proteomic profiling of paradoxical low-flow low-gradient aortic stenosis myocardium.

Patients with severe aortic stenosis (AS), low transvalvular flow (LF) and low gradient (LG) with normal ejection fraction (EF)-are referred to as paradoxical LF-LG AS (PLF-LG). PLF-LG patients develop more advanced heart failure symptoms and have a worse prognosis than patients with normal EF and high-gradient AS (NEF-HG). Despite its clinical relevance, the mechanisms underlying PLF-LG are still poorly understood. Left ventricular (LV) myocardial biopsies of PLF-LG (n = 5) and NEF-HG patients (n = 6), obtained during transcatheter aortic valve implantation, were analyzed by LC-MS/MS after sequential extraction of cellular and extracellular matrix (ECM) proteins using a three-step extraction method. Proteomic data are available via ProteomeXchange with identifier PXD055391. 73 cellular proteins were differentially abundant between the 2 groups. Among these, a network of proteins related to muscle contraction and arrhythmogenic cardiomyopathy (e.g., cTnI, FKBP1A and CACNA2D1) was found in PLF-LG. Extracellularly, upregulated proteins in PLF-LG were related to ATP synthesis and oxidative phosphorylation (e.g., ATP5PF, COX5B and UQCRB). Interestingly, we observed a 1.3-fold increase in cyclophilin A (CyPA), proinflammatory cytokine, in the extracellular extracts of PLF-LG AS patients (p < 0.05). Consistently, immunohistochemical analysis confirmed its extracellular localization in PLF-LG AS LV sections along with an increase in its receptor, CD147, compared to the NEF-HG AS patients. Levels of core ECM proteins, namely collagens and proteoglycans, were comparable between groups. Our study pinpointed novel candidates and processes with potential relevance in the pathophysiology of PLF-LG. The role of CyPA in particular warrants further investigation.

Difference in Cardiac Response after Transcatheter Aortic Valve Implantation according to Flow and Gradient Pattern.

In patients undergoing transcatheter aortic valve implantation (TAVI) for severe aortic stenosis (AS), data on the differences in subsequent cardiac structure and function among stratified groups with flow gradient patterns through the aortic valve are insufficient. In this large multicenter study, 4,523 patients undergoing TAVI for severe AS between 2013 and 2019 were divided into 3 groups according to the following criteria: (1) high-gradient AS (HG-AS) (mean pressure gradient [MPG] ≥40 mmHg), (2) classical low-flow low-gradient AS (cLFLG-AS) (MPG <40 mmHg, left ventricular [LV] ejection fraction [LVEF] <50%), and (3) paradoxical low-flow low-gradient AS (pLFLG-AS) (MPG <40 mmHg, LVEF ≥50% but stroke volume index [SVi] <35 mL/m2). Echocardiography was performed at baseline, post-procedure, and 1 year post-TAVI. 3,697, 507, and 319 patients had HG-AS, cLFLG-AS, and pLFLG-AS, respectively. After adjusting for clinical factors, cLFLG-AS and pLFLG-AS had an approximately 1.5-fold higher 2-year all-cause mortality compared with HG-AS. During 1 year following TAVI, compared with HG-AS, cLFLG-AS showed greater reduction of LV systolic diameter (LVDs) and LV diastolic diameter (LVDd) and greater increase of LVEF (p<0.001 for all), and changes in LV mass index (LVMi) and SVi were comparable (p=0.915 and p=0.821, respectively). However, pLFLG-AS demonstrated less reduction of LVDs and LVDd (p=0.039 and p=0.001, respectively), less improvement of LVEF and LVMi (p=0.045 and p<0.001, respectively), and comparable change in SVi (p=0.364). During 1 year post-TAVI, compared with HG-AS, cLFLG-AS achieves smaller LV diameters, greater increase in LVEF, and comparable regression of LVMi, whereas pLFLG-AS does not.

Natural History of Mitral Regurgitation After Transcatheter Aortic Valve Implantation

BackgroundThis study sought to determine the impact of mitral regurgitation (MR) on outcomes after transcatheter aortic valve implantation (TAVI). MethodsThis was an observational study of TAVI for aortic stenosis (AS) from November 2012 to December 2021; 25% of patients were excluded because post-TAVI echocardiograms were unavailable. Excluded patients had a higher Society of Thoracic Surgeons predicted risk of mortality score than included patients (5.6% vs 4.9%). Patients were dichotomized according to the severity of pre-TAVI MR: < moderate vs ≥ moderate. ResultsA total of 2250 patients underwent TAVI, of whom 329 (14.6%) had MR ≥ moderate before TAVI. Baseline MR ≥ moderate was associated with reduced survival (46.2% for MR ≥ moderate vs 58.7% for MR < moderate; P < .001) and a higher incidence of heart failure readmission at 5 years after TAVI; 11% of patients had progression or persistence of MR ≥ moderate at 1 year after TAVI, which was also associated with reduced survival. On multivariable logistic regression, increasing age, women, lower ejection fraction, prior acute coronary syndrome, concomitant aortic insufficiency ≥ moderate, low-flow low-gradient AS, pulmonary hypertension, baseline tricuspid regurgitation ≥ moderate, and lower mean pre-TAVI aortic transvalvular pressure gradient were associated with progression or persistence of MR ≥ moderate at 1 year after TAVI, whereas procedural variables and postprocedural complications were not. ConclusionsSignificant MR before and after TAVI was associated with reduced survival. Whereas various clinical variables were associated with significant MR after TAVI, periprocedural variables were not. Evolution of MR must be carefully surveilled after TAVI, and more data are needed to establish guidelines for managing mixed AS and MR.

A novel functional index, aortic-valve-coefficient, for assessing aortic-stenosis in patients undergoing TAVR: A prospective-pilot study

BackgroundEvaluating the severity of aortic stenosis (AS) can be challenging, particularly in patients with low-gradient (LG, Δp < 40 mmHg) AS. Objective: This study aims to improve the accuracy of assessing severity of AS using a novel functional index- Aortic Valve Coefficient (AVC). The AVC is defined as ratio of mean transvalvular pressure-drop (Δp) to the proximal dynamic pressure (1/2 × blood density × VLVOT2; VLVOT: left ventricular outflow tract peak velocity). Hypothesis: AVC, developed from fundamental fluid dynamic principles, is a better index for accessing AS severity as it incorporates square of VLVOT and downstream pressure recovery. MethodsThis pilot prospective study enrolled 47 patients undergoing TAVR for AS. Using cardiac-catheterization-measured Δp and echocardiography-Doppler-derived VLVOT, AVC was evaluated. Pre- and post-TAVR pressure-velocity measurements were obtained, resulting in a dataset with 78 data points, including 32 data points specifically linked to LG AS. Linear regression analysis was performed to correlate AVC with Δp, VLVOT and aortic-valve-area. Welch 2-sample t-test was carried out to compare the means of AVC against aortic-valve-area. ResultsModerate correlation (r = 0.85) was observed between AVC and aortic-valve-area indicating AVC could be a prospective index. However, correlation decreased (r = 0.75) in LG AS patients, indicating increased discordancy. Comparing AVC and aortic-valve-area in LG AS patients with left ventricular ejection fraction (LVEF) < 50 % and LVEF ≥50 %, t-test showed that AVC values are significantly different (p < 0.05) as compared to aortic-valve-area (p = 0.48). ConclusionAVC, a novel index, has the potential to improve assessment of AS severity and clinical decision making for treating patients with AS. Condensed abstractComplex hemodynamics, such as paradoxical “low-flow low-gradient (LG)” Aortic stenosis (AS) can be difficult to diagnose. Currently, mean transvalvular pressure-drop and flow-derived aortic-valve-area assess AS severity. Aortic valve coefficient (AVC) is a novel index which combines both pressure-drop and flow measurements to assess the severity of AS. A total of 47 patients (72 data points) were studied undergoing TAVR. In LG AS patients, t-test comparing left ventricular ejection fraction (LVEF) < 50 % and LVEF ≥50 % showed that AVC are significantly different (p < 0.05) as compared to aortic-valve-area (p = 0.48). Therefore, AVC could be a better index.

Prognostication and Interventional Guidance Using Acceleration-Ejection Time Ratio in Undifferentiated Paradoxical Low-Flow Low-Gradient Aortic Stenosis

BackgroundStudies in paradoxical low-flow low-gradient aortic stenosis (PLFAS) have demonstrated conflicting outcomes with variable survival advantage from aortic valve replacement (AVR). PLFAS is a heterogeneous composition of patients with uncertainty regarding true stenosis severity that continues to confound decision-making for AVR. ObjectivesThe purpose of this study was to investigate the utility of the Doppler acceleration (AT) to ejection (ET) time ratio (AT:ET) for prediction of prognosis and benefit from AVR in undifferentiated PLFAS. MethodsPatients with echocardiographic findings of PLFAS (aortic valve area <1.0 cm2 or indexed aortic valve area <0.6 cm2/m2, mean gradient <40 mm Hg, indexed stroke volume <35 mL/m2, and left ventricular ejection fraction ≥50%) were identified and grouped according to an AT:ET cutoff of 0.35. The primary outcome was a 5-year composite of cardiac mortality or AVR. Secondary outcomes included the individual components of the primary endpoint and all-cause mortality at 5 years. Effect of AVR was analyzed in the AT:ET <0.35 and ≥0.35 groups. ResultsA total of 171 PLFAS patients (median age 77.0 years, 57% women) were followed for a median of 8.9 years. AT:ET ≥0.35 was an independent predictor of the primary outcome (HR: 4.77 [95% CI: 2.94-7.75]; P < 0.001) with incremental value over standard indices of stenosis severity (net reclassification improvement: 0.57 [95% CI: 0.14-0.84]). AT:ET ≥0.35 also remained predictive of increased cardiac death (HR: 2.91 [95% CI: 1.47-5.76]; P = 0.002) and AVR (HR: 8.45 [95% CI: 4.16-17.1]; P < 0.001), respectively, following competing risk analysis. No difference in all-cause mortality was observed. AVR in the AT:ET ≥0.35 group was associated with significant reductions in 5-year cardiac (HR: 0.09 [95% CI: 0.02-0.36]; P < 0.001) and all-cause mortality (HR: 0.16 [95% CI: 0.07-0.38]; P < 0.001). No improvement in survival from AVR was demonstrated in AT:ET <0.35 patients. ConclusionsAT:ET ≥0.35 in PLFAS predicts poorer outcomes and/or need for AVR. In undifferentiated PLFAS patients, AT:ET may have a potential role in improving patient selection for prognostic AVR.

Sex Differences in Aortic Stenosis: From the Pathophysiology to the Intervention, Current Challenges, and Future Perspectives.

Calcific aortic stenosis (AS) is a major cause of morbidity and mortality in high-income countries. AS presents sex-specific features impacting pathophysiology, outcomes, and management strategies. In women, AS often manifests with a high valvular fibrotic burden, small valvular annuli, concentric left ventricular (LV) remodeling/hypertrophy, and, frequently, supernormal LV ejection fraction coupled with diastolic dysfunction. Paradoxical low-flow low-gradient AS epitomizes these traits, posing significant challenges post-aortic valve replacement due to limited positive remodeling and significant risk of patient-prosthesis mismatch. Conversely, men present more commonly with LV dilatation and dysfunction, indicating the phenotype of classical low-flow low-gradient AS, i.e., with decreased LV ejection fraction. However, these distinctions have not been fully incorporated into guidelines for AS management. The only treatment for AS is aortic valve replacement; women are frequently referred late, leading to increased heart damage caused by AS. Therefore, it is important to reassess surgical planning and timing to minimize irreversible cardiac damage in women. The integrity and the consideration of sex differences in the management of AS is critical. Further research, including sufficient representation of women, is needed to investigate these differences and to develop individualized, sex-specific management strategies.

Transcatheter aortic valve replacement outcomes in patients with high gradient versus low ejection fraction low gradient severe aortic stenosis: A meta-analysis of randomized controlled trials

BackgroundThe outcome of Low Flow-Low Gradient (LF-LG) severe aortic stenosis (AS) patients who underwent Transcatheter Aortic Valve Replacement (TAVR) procedure is not well defined. We conducted a systematic review of the literature to compare the outcomes of TAVR in LF-LG AS patients to the more traditional high gradient (HG) aortic stenosis. MethodsWe comprehensively searched for controlled randomized and non-randomized studies from 4 online databases. We are presenting the data using risk ratios (95 % confidence intervals) and measuring heterogeneity using Higgins' I2 index. ResultsOur analysis included 4380 patients with 3425 HG patients and 955 LF-LG patients from 6 cohort (5 retrospective and 1 prospective) studies. When compared to LFLG; TAVR was associated with significantly lower 30 days mortality in HG patients (5.1 % vs 7.4 %; relative risk [RR]: 0.55; 95 % confidence interval [CI]: 0.35 to 0.86; p < 0.01). Similar findings were also observed in 12-month cardiovascular (CV) mortality (5.5 % vs. 10.4 %; RR: 0.47; 95 % CI: 0.38 to 0.60; p < 0.01 and 12-month all-cause mortality (15.9 % vs 20.9 %; RR: 0.70; 95 % CI: 0.49 to 1.00; p < 0.05). There was no significant difference in myocardial infarction (MI) after TAVR between HG and LF-LG at 30 days (0.16 % vs. 0.95 %; p < 0.09) or 12 months (0.43 % vs. 0.95 %; p = 0.20). Similarly, there was no difference in stroke rates at 30 days (2.9 % vs. 2.86 %) or at 12 months (3.6 % vs. 3.06 %). Conclusions and relevancePatients with LF-LG severe AS who underwent TAVR had worse 1-year all-cause mortality, 30-day all-cause, and 1-year CV mortality when compared to TAVR in HG severe AS. There was no difference in MI or stroke rates. Therefore, with heart team discussion and informed patient decision regarding the risk and benefit, TAVR would still offer better outcomes in LFLG AS compared to conservative medical management.

Prognostic Impact of High-Molecular-Weight von Willebrand Factor Multimer Ratio in Classical Low-Flow Low-Gradient Aortic Stenosis.

High-molecular-weight (HMW) von Willebrand factor (VWF) multimer deficiency occurs in classical low-flow, low-gradient (LF/LG) aortic stenosis (AS) due to shear force-induced proteolysis. The prognostic value of HMW VWF multimer deficiency is unknown. Therefore, we sought to evaluate the impact of HMW VWF multimer deficiency on clinical outcome. In this prospective research study, a total of 83 patients with classical LF/LG AS were included. All patients underwent dobutamine stress echocardiography to distinguish true-severe (TS) from pseudo-severe (PS) classical LF/LG AS. HMW VWF multimer ratio was calculated using densitometric Western blot band quantification. The primary endpoint was all-cause mortality. Mean age was 79 ± 9 years, and TS classical LF/LG AS was diagnosed in 73% (n = 61) and PS classical LF/LG AS in 27% (n = 22) of all patients. Forty-six patients underwent aortic valve replacement (AVR) and 37 were treated conservatively. During a mean follow-up of 27 ± 17 months, 47 deaths occurred. Major bleeding complications after AVR (10/46; 22%) were more common in patients with HMW VWF multimer ratio &lt;1 (8/17; 47%) in comparison to patients with a normal multimer pattern (2/29; 7%) at baseline (p = 0.003). In a multivariable Cox regression analysis, HMW VWF multimer deficiency was a predictor of all-cause mortality (HR: 3.02 [95% CI: 1.31-6.96], p = 0.009) in the entire cohort. This association was driven by higher mortality rates in the AVR group (multivariable-adjusted HR: 9.4; 95% CI 2.0-43.4, p = 0.004). This is the first study to demonstrate the predictive value of HMW VWF multimer ratio for risk stratification in patients with classical LF/LG AS. HMW VWF multimer deficiency was associated with an increased risk of all-cause mortality and major bleeding complications after AVR.

Diagnostic Challenges in Aortic Stenosis.

Aortic stenosis (AS) is the most prevalent degenerative valvular disease in western countries. Transthoracic echocardiography (TTE) is considered, nowadays, to be the main imaging technique for the work-up of AS due to high availability, safety, low cost, and excellent capacity to evaluate aortic valve (AV) morphology and function. Despite the diagnosis of AS being considered straightforward for a very long time, based on high gradients and reduced aortic valve area (AVA), many patients with AS represent a real dilemma for cardiologist. On the one hand, the acoustic window may be inadequate and the TTE limited in some cases. On the other hand, a growing body of evidence shows that patients with low gradients (due to systolic dysfunction, concentric hypertrophy or coexistence of another valve disease such as mitral stenosis or regurgitation) may develop severe AS (low-flow low-gradient severe AS) with a similar or even worse prognosis. The use of complementary imaging techniques such as transesophageal echocardiography (TEE), multidetector computed tomography (MDTC), or cardiac magnetic resonance (CMR) plays a key role in such scenarios. The aim of this review is to summarize the diagnostic challenges associated with patients with AS and the advantages of a comprehensive multimodality cardiac imaging (MCI) approach to reach a precise grading of the disease, a crucial factor to warrant an adequate management of patients.

Right ventricular to pulmonary artery coupling in patients with different types of aortic stenosis undergoing TAVI.

Right ventricular (RV) dysfunction in patients undergoing transcatheter aortic valve implantation (TAVI) for aortic stenosis (AS) has long been disregarded. We aimed to assess the predictive value of RV to pulmonary artery coupling (RV/PAc), defined as tricuspid annular plane systolic excursion to systolic pulmonary artery pressure, on mortality in different flow types of AS after TAVI. All patients undergoing TAVI for AS at our centre between 2018 and 2020 were assessed; 862 patients were analysed. The cohort was dichotomized using a ROC analysis (cut-off 0.512mm/mmHg), into 429 patients with preserved and 433 patients with reduced RV/PAc. Reduced RV/PAc was associated with male sex and a higher rate of comorbidities. Short-term VARC-3 endpoints and NYHA classes at follow-up were comparable. Reduced RV/PAc was associated with higher 2-year all-cause mortality (35.0% [30.3-39.3%] vs. 15.4% [11.9-18.7%], hazard ratio 2.5 [1.9-3.4], p < 0.001). Cardiovascular mortality was almost tripled. Results were consistent after statistical adjustment and in a multivariate model. Sub-analyses of AS flow types revealed lower RV/PAc in classical and paradoxical low-flow low-gradient AS, with the majority having reduced RV/PAc (74% and 59%). RV/PAc retained its predictive value in these subgroups. RV dysfunction defined by low RV/PAc is a strong mortality predictor after TAVI independent of flow group. It should be incorporated in future TAVI risk assessment.

A Complex Case with a Completely Percutaneous Solution: Treatment of a Severe Calcific Left Main in a Patient with Low-Flow Low-Gradient Aortic Stenosis

Background: This case study explores an integrated approach to managing a complex cardiac condition, presenting a comprehensive single-session intervention. This includes balloon valvuloplasty using a Nucleus 18 mm balloon, complex angioplasty with rotational atherectomy (rotablator) targeting calcified lesions in the left main and left anterior descending artery, and Transcatheter Aortic Valve Implantation (TAVI) with a 23 mm Sapien 3 valve, all performed on an 81-year-old woman. Furthermore, this report underscores the strategic left atrial appendage closure conducted three months post-procedure due to the patient’s elevated hemorrhagic risk. Case presentation: Facing critical coronary and valvular pathologies, the patient underwent a meticulously planned, single-session intervention. The process began with a balloon valvuloplasty using a Nucleus 18 mm balloon to address the aortic stenosis. This was followed by a high-risk angioplasty, during which the Impella CP device provided hemodynamic support and rotational atherectomy was employed to address the calcified coronary artery disease effectively. The same session saw the successful execution of TAVI using a 23 mm Sapien 3 valve. The comprehensive approach notably diminished procedural complications, illustrating the benefits of an integrated treatment pathway in managing high-risk patients. Three months later, the patient underwent a left atrial appendage closure, a critical move considering her high risk of hemorrhage. This procedure also provided an opportunity to assess the favorable outcomes of the previous angioplasty. Conclusion: This case validates the feasibility and efficacy of performing multiple advanced percutaneous interventions in a single session for high-risk cardiac patients. It underscores the crucial role of innovative and personalized treatment strategies in improving patient outcomes, particularly in complex clinical scenarios. Moreover, the case exemplifies the essential relationship between immediate, comprehensive intervention and subsequent follow-up procedures in ensuring optimal long-term patient care.

Long-Term Outcomes of Aortic Stenosis Patients with Different Flow/Gradient Patterns Undergoing Transcatheter Aortic Valve Implantation.

Background: Few data exist on the comparative long-term outcomes of severe aortic stenosis (AS) patients with different flow-gradient patterns undergoing transcatheter aortic valve implantation (TAVI). This study sought to evaluate the impact of the pre-TAVI flow-gradient pattern on long-term clinical outcomes after TAVI and assess changes in the left ventricular ejection fraction (LVEF) of different subtypes of AS patients following TAVI. Methods: Consecutive patients with severe AS undergoing TAVI in our institution were screened and prospectively enrolled. Patients were divided into four subgroups according to pre-TAVI flow/gradient pattern: (i) low flow-low gradient (LF-LG): stroke volume indexed (SVi) ≤ 35 mL/m2 and mean gradient (MG) < 40 mmHg); (ii) normal flow-low gradient (NF-LG): SVi > 35 mL/m2 and MG < 40 mmHg; (iii) low flow-high gradient (LF-HG): Svi 35 mL/m2 and MG ≥ 40 mmHg and (iv) normal flow-high gradient (NF-HG): SVi > 35 mL/m2 and MG ≥ 40 mmHg. Transthoracic echocardiography was repeated at 1-year follow-up. Clinical follow-up was obtained at 12 months, and yearly thereafter until 5-year follow-up was complete for all patients. Results: A total of 272 patients with complete echocardiographic and clinical follow-up were included in our analysis. Their mean age was 80 ± 7 years and the majority of patients (N = 138, 50.8%) were women. 62 patients (22.8% of the study population) were distributed in the LF-LG group, 98 patients (36%) were LF-HG patients, 95 patients (34.9%) were NF-HG, and 17 patients (6.3%) were NF-LG. There was a greater prevalence of comorbidities among LF-LG AS patients. One-year all-cause mortality differed significantly between the four subgroups of AS patients (log-rank p: 0.022) and was more prevalent among LF-LG patients (25.8%) compared to LF-HG (11.3%), NF-HG (6.3%) and NF-LG patients (18.8%). At 5-year follow-up, global mortality remained persistently higher among LF-LG patients (64.5%) compared to LF-HG (47.9%), NF-HG (42.9%), and NF-LG patients (58.8%) (log-rank p: 0.029). At multivariable Cox hazard regression analysis, baseline SVi (HR: 0.951, 95% C.I.; 0.918-0.984), the presence of at least moderate tricuspid regurgitation at baseline (HR: 3.091, 95% C.I: 1.645-5.809) and at least moderate paravalvular leak (PVL) post-TAVI (HR: 1.456, 95% C.I.: 1.106-1.792) were significant independent predictors of late global mortality. LF-LG patients and LF-HG patients exhibited a significant increase in LVEF at 1-year follow-up. A lower LVEF (p < 0.001) and a lower Svi (p < 0.001) at baseline were associated with LVEF improvement at 1-year. Conclusions: Patients with LF-LG AS have acceptable 1-year outcomes with significant improvement in LVEF at 1-year follow-up, but exhibit exceedingly high 5-year mortality following TAVI. The presence of low transvalvular flow and at least moderate tricuspid regurgitation at baseline and significant paravalvular leak post-TAVI were associated with poorer long-term outcomes in the entire cohort of AS patients. The presence of a low LVEF or a low SVi predicts LVEF improvement at 1-year.

Myocardial sodium-glucose cotransporter 2 expression and cardiac remodelling in patients with severe aortic stenosis: The BIO-AS study.

Cardiac remodelling plays a major role in the prognosis of patients with aortic stenosis (AS) and could impact the benefits of aortic valve replacement. Our study aimed to evaluate the expression of sodium-glucose cotransporter 2 (SGLT2) gene and protein in patients with severe AS stratified in high gradient (HG) and low flow-low gradient (LF-LG) AS and its association with cardiac functional impairments. Gene expression and protein levels of main biomarkers of cardiac fibrosis (galectin-3, sST2, serpin-4, procollagen type I amino-terminal peptide, procollagen type I carboxy-terminal propeptide, collagen, transforming growth factor [TGF]-β), inflammation (growth differentiation factor-15, interleukin-6, nuclear factor-κB [NF-κB]), oxidative stress (superoxide dismutase 1 [SOD1] and 2 [SOD2]), and cardiac metabolism (sodium-hydrogen exchanger, peroxisome proliferator-activated receptor [PPAR]-α, PPAR-γ, glucose transporter 1 [GLUT1] and 4 [GLUT4]) were evaluated in blood samples and heart biopsies of 45 patients with AS. Our study showed SGLT2 gene and protein hyper-expression in patients with LF-LG AS, compared to controls and HG AS (p < 0.05). These differences remained significant even after adjusting for age, gender, body mass index, history of diabetes mellitus, arterial hypertension, and coronary artery disease. SGLT2 gene expression was positively correlated with: (i) TGF-β (r = 0.72, p < 0.001) and collagen (r = 0.73, p < 0.001) as markers of fibrosis; (ii) NF-κB (r = 0.36, p < 0.01) and myocardial interleukin-6 (r = 0.68, p < 0.001) as markers of inflammation: (iii) SOD2 (r = -0.38, p < 0.006) as a marker of oxidative stress; (iv) GLUT4 (r = 0.33, p < 0.02) and PPAR-α (r = 0.36, p < 0.01) as markers of cardiac metabolism. In patients with LF-LG AS, SGLT2 gene and protein were hyper-expressed in cardiomyocytes and associated with myocardial fibrosis, inflammation, and oxidative stress.

Paradoxical low flow-low gradient aortic stenosis: lights and shadows

Paradoxical low flow-low gradient aortic valve stenosis (AVS) is an increasing phenotype in the general population, particularly after the seventh decade of life. It is an AVS in which, despite the preserved ejection fraction, the mean transvalvular gradient is not suggestive of severe AVS (<40 mmHg). The pathophysiology is often intertwined with conditions resulting in heart failure with preserved ejection fraction, such as arterial hypertension and cardiac amyloidosis. Its management is rather controversial about the diagnosis and therapeutic management. The aims of this focus are: to clarify the role and reliability of the main available diagnostic methods, the efficacy of surgical and percutaneous treatments, and to develop a diagnostic-therapeutic algorithm for managing this condition in clinical practice. This algorithm will involve a multi-parametric evaluation, integrating standard echocardiographic assessment with three-dimensional planimetric valve area calculation, determination of the energy loss index), and calcium score calculation by computed tomography scan. This approach aims to ascertain the severity of the stenosis and determine the appropriate therapeutic management.

Carotid Duplex Ultrasonography to Assess Severity of Low-Flow Low-Gradient Aortic Stenosis

BackgroundPatients with low-flow, low-gradient aortic valve stenosis constitute a substantial subset of all severe aortic stenosis patients. However, assessment of true severity of these patients can be challenging. In this analysis, we study the utility of the common carotid artery waveforms to distinguish true from pseudo-severe low-flow low-gradient aortic stenosis. MethodsThis is an observational analysis that included patients who underwent a transthoracic echocardiogram (TTE) and duplex carotid ultrasonography (DCUS) and had low-flow, low-gradient aortic stenosis with reduced left ventricular ejection fraction (LVEF) on the index TTE (LVEF <50%, calculated aortic valve area [AVA] of ≤1.0 cm2, mean and peak gradient of <40 and <64 mm Hg, respectively, and stroke volume index <35 mL/m2). Patients were classified as pseudo-severe and true-severe aortic stenosis based on additional subsequent testing. Differences in various TTE and DCUS waveform parameters across the aortic valve and the common carotid artery were compared between the 2 groups. ResultsThe study included 30 patients (60 carotid arteries). Fifteen patients were categorized as pseudo-severe and 15 as true severe aortic stenosis. There were no significant differences in calculated AVA, LVEF, stroke volume/stroke volume index, and Doppler Velocity Index in the 2 groups. Mean and peak gradient were higher in patients with true-severe aortic stenosis. Carotid acceleration time (cAT) was significantly prolonged in patients with true-severe compared with pseudo-severe aortic stenosis. A cAT ≥80 ms was 83.3% sensitive and 83.3% specific for true-severe aortic stenosis. ConclusioncAT acceleration time may be used to distinguish true from pseudo-severe low-flow, low-gradient aortic valve stenosis.