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Background: In patients with low-gradient (LG) aortic stenosis (AS), confirming disease severity and indication of intervention often requires dobutamine stress echocardiography (DSE) or aortic valve calcium scoring by computed tomography. We hypothesized that the mean transvalvular pressure gradient to effective orifice area ratio (MG/EOA, in mm Hg/cm2) measured during rest echocardiography identifies true-severe AS (TSAS) and is associated with clinical outcomes in patients with low-flow, LG-AS. Objectives: The purpose of this study was to evaluate the diagnostic and prognostic value of MG/EOA ratio. Methods: The diagnostic accuracy of MG/EOA ratio to identify TSAS was retrospectively assessed in: 1) an in vitro data set obtained in a circulatory model including 93 experimental conditions; and 2) an in vivo data set of 188 patients from the TOPAS (True or Pseudo-Severe Aortic Stenosis) study (NCT01835028). Receiver operating characteristic curves were used to assess the diagnostic accuracy of MG/EOA ratio for identifying TSAS, and Cox proportional hazards regression analyses were performed to assess its association with clinical outcomes. Results: The optimal cutoff of MG/EOA ratio to identify TSAS in patients with low-flow, LG-AS was ≥25 mm Hg/cm2 (correct classification 85%), as well as in vitro (100%). During a median follow-up of 1.41 ± 0.75 years, 146 (78%) patients met the composite endpoint of aortic valve replacement or all-cause mortality. A MG/EOA ratio ≥25 mm Hg/cm2 was independently associated with an increased risk of the composite endpoint (adjusted HR: 2.36 [95% CI: 1.63-3.42], P < 0.001). The Harell's C-index of MG/EOA was 0.68, equaling projected EOA (0.67) measured by DSE. Conclusions: MG/EOA ratio can be useful in low-flow, LG-AS to confirm AS severity and may complement DSE or aortic valve calcium scoring.

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BACKGROUND: Calcification score by cardiac computed tomography (CT) is required for diagnosis of paradoxical low-flow/low-gradient (PLFLG) aortic stenosis (AS). According to the guideline, velocity ratio (VR) < 0.25 by echocardiography is defined as severe AS, but utility of VR in patients with PLFLG AS remains unknown. This retrospective study was therefore conducted to investigate the utility of VR for a diagnosis of severe AS based on CT in patients with PLFLG AS. METHODS: We studied 58 patients with PLFLG AS. Severity of AS was defined as calcium score derived from cardiac CT. RESULTS: Of the 58 patients, 28 (48.3%) were diagnosed with severe AS based on CT, while 23 of them (82.1%) had VR < 0.25. It was noteworthy that receiver operating characteristic curve analysis showed that the optimal VR cutoff value for a diagnosis of severe AS was 0.25, with an area under the curve of 0.870 (P < 0.001). Sensitivity, specificity, positive predictive value, and negative predictive value of VR < 0.25 for a diagnosis of severe AS were 82.1%, 86.7%, 85.2% and 83.9%, respectively. Furthermore, patients who match the value of VR and severity of AS based on CT had higher prevalence of atrial fibrillation, higher serum brain natriuretic peptide concentration, larger left ventricular end-diastolic volume, and left ventricular stroke volume index. CONCLUSION: The measurement of VR is simple, and VR < 0.25 can be used for diagnosis of patients with PLFLG AS as severe. Our findings may thus have clinical implications for routine clinical practice.

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BACKGROUND: The 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. METHODS: We 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. RESULTS: Our 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 RELEVANCE: Patients 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.

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IMPORTANCE: Guidelines recommend the use of dobutamine stress echocardiography (DSE) in patients with low-gradient aortic stenosis (AS) and left ventricular ejection fraction (LVEF) <50%. However, a paucity of DSE data exists when LVEF >35%. OBJECTIVE: To examine the diagnostic accuracy of DSE in patients with low-gradient AS with a wide range of LVEF and to examine the interaction between the diagnostic accuracy of DSE and LVEF. DESIGN, SETTING, AND PARTICIPANTS: Patients with mean gradient <40 mm Hg, aortic valve area <1.0 cm2, and stroke volume index ≤35 mL/m2 undergoing DSE and cardiac computer tomography (C-CT) were identified from 3 prospectively collected patient cohorts and stratified according to LVEF: LVEF<35%, LVEF 35% to 50%, and LVEF>50%. EXPOSURE: Dobutamine stress echocardiography and C-CT were performed on patients with low-gradient AS. MAIN OUTCOMES AND MEASURES: Severe AS was defined as aortic valve calcification score ≥2,000 arbitrary units (AU) among men and ≥1,200 AU for women on C-CT. RESULTS: Of 221 patients included in the study, 78 (35%) presented with LVEF <35%, 67 (30%) with LVEF 35% to 50%, and 76 (34%) with LVEF >50%. Mean-gradient and aortic valve peak velocity during DSE showed significant diagnostic heterogeneity between LVEF groups, being most precise when LVEF <35% (both areas under the curve [AUC] = 0.90), albeit with optimal thresholds of 30 mm Hg and 377 cm/sec and a limited diagnostic yield in patients with LVEF ≥35% (AUC = 0.67 and 0.66 in LVEF 35% to 50% and AUC = 0.65 and 0.60 in LVEF ≥50%). Using guideline thresholds led to a sensitivity/specificity of 49%/84% for all patients with LVEF <50%. CONCLUSION AND RELEVANCE: While DSE is safe and leads to an increase in stroke volume in patients with low-gradient AS regardless of LVEF, the association between DSE gradients and AS severity assessed by C-CT demonstrates important heterogeneity depending on LVEF, with the highest accuracy in patients with LVEF <35%.

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Current guidelines of aortic stenosis (AS) management focus on valve parameters, LV systolic dysfunction, and symptoms; however, emerging data suggest that there may be benefit of aortic valve replacement before it becomes severe by present criteria. Myocardial assessment using novel multimodality imaging techniques exhibits subclinical myocardial injury and remodeling at various stages before guideline-directed interventions, which predicts adverse outcomes. This raises the question of whether implementing serial myocardial assessment should become part of the standard appraisal, thereby identifying high-risk patients aiming to minimize adverse outcomes.

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Rest and stress echocardiography (SE) play a fundamental role in the evaluation of aortic valve stenosis (AS). According to the current guidelines for the echocardiographic evaluation of patients with aortic stenosis, four broad categories can be defined: high-gradient AS (mean gradient ≥ 40 mmHg, peak velocity ≥ 4 m/s, aortic valve area (AVA) ≤ 1 cm2 or indexed AVA ≤ 0.6 cm2/m2); low-flow, low-gradient AS with reduced ejection fraction (mean gradient < 40 mmHg, AVA ≤ 1 cm2, left ventricle ejection fraction (LVEF) < 50%, stroke volume index (Svi) ≤ 35 mL/m2); low-flow, low-gradient AS with preserved ejection fraction (mean gradient < 40 mmHg, AVA ≤ 1 cm2, LVEF ≥ 50%, SVi ≤ 35 mL/m2); and normal-flow, low-gradient AS with preserved ejection fraction (mean gradient < 40 mmHg, AVA ≤ 1 cm2, indexed AVA ≤ 0.6 cm2/m2, LVEF ≥ 50%, SVi > 35 mL/m2). Aortic valve replacement (AVR) is indicated with the onset of symptoms development or LVEF reduction. However, there is often mismatch between resting transthoracic echocardiography findings and patient's symptoms. In these discordant cases, SE and CT calcium scoring are among the indicated methods to guide the management decision making. Additionally, due to the increasing evidence that in asymptomatic severe aortic stenosis an early AVR instead of conservative treatment is associated with better outcomes, SE can help identify those that would benefit from an early AVR by revealing markers of poor prognosis. Low-flow, low-gradient AS represents a challenge both in diagnosis and in therapeutic management. Low-dose dobutamine SE is the recommended method to distinguish true-severe from pseudo-severe stenosis and assess the existence of flow (contractile) reserve to appropriately guide the need for intervention in these patients.

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AIMS: Paradoxical low-flow, low-gradient aortic stenosis (pLFLG AS) may represent a diagnostic challenge, and its pathophysiology is complex. While left ventricular (LV) systolic function is preserved, right ventricular dysfunction (RVD) and consecutive LV underfilling may contribute to low-flow and reduced stroke volume index, and to adverse outcomes following transcatheter aortic valve implantation (TAVI). The aim of this study was to evaluate the potential role of RVD in pLFLG AS, and to assess the impact of pre-procedural RVD on clinical outcomes after TAVI in patients with pLFLG AS. METHODS AND RESULTS: Out of 2739 native AS patients, who received TAVI at the University of Cologne Heart Center between March 2013 and June 2021, 114 patients displayed pLFLG AS and were included in this study. Right ventricular (RV) function was assessed by transthoracic echocardiography, and a fractional area change (FAC) ≤35% and/or a tricuspid annular plane systolic excursion (TAPSE) <18 mm determined RVD. In addition, the TAPSE/systolic pulmonary artery pressure ratio (TAPSE/sPAP) was monitored as a measure of RV-pulmonary arterial (PA) coupling. An impaired FAC and TAPSE was present in 21.9% and 45.6% of patients, respectively, identifying RVD in 50.0%. RVD (p = 0.016), reduced FAC (p = 0.049), reduced TAPSE (p = 0.035) and impaired RV-PA coupling (TAPSE/sPAP ratio <0.31 mm/mmHg; p = 0.009) were associated with significantly higher all-cause mortality compared to patients with normal RV function. After adjustment for sex, age, body mass index, EuroSCORE II, previous myocardial infarction and mitral regurgitation, independent predictors for all-cause mortality were FAC, sPAP, TAPSE/sPAP ratio, right atrial area, RV diameter and tricuspid regurgitation. CONCLUSIONS: Adverse RV remodelling, RVD and impaired RV-PA coupling provide an explanation for low-flow and reduced stroke volume index in a subset of patients with pLFLG AS, and are associated with excess mortality after TAVI.

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Moderate aortic stenosis is associated with a worse prognosis than milder degrees. Pathophysiologically, this condition in a dysfunctional ventricle could lead to a further mechanism of haemodynamic worsening, so its treatment should lead to clinical advantages for the patient. The low risk of complications associated with percutaneous correction of aortic valve disease (transcatheter aortic valve implantation) should also be considered, which would seem to favour an interventional approach even in the aforementioned condition. However, sparse data and small population studies make this approach still controversial. Three randomized controlled trials are underway to shed definitive light on the topic.

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Background: D2 aortic stenosis (AS) is the highest risk AS subtype with worse operative and mortality outcomes. This study aimed to investigate the quality of life (QoL) and left ventricular ejection fraction (LVEF) in patients with classic (D2 subtype) low-flow/low-gradient AS who underwent transcatheter aortic valve replacement (TAVR). Methods: In total, 634 patients with severe AS underwent TAVR at our institution from 2014 to 2020, of whom 76 met criteria for classic D2 AS with reduced LVEF. Echocardiographic and clinical outcomes including mortality, stroke, pacemaker placement (PPM), and readmission at baseline were compared with those at 30 days and 1 year. QoL data were extracted from the Kansas City Cardiomyopathy Questionnaire (KCCQ-12). Results: The average baseline Society of Thoracic Surgeons risk score for patients with D2 AS was 7.66 ± 6.76. Patients with D2 AS reported improved QoL post-TAVR. The average baseline KCCQ-12 score was 39.5 ± 20, with improvement to 68.9 ± 20.6 at 30 days (P < .01) and 74.9 ± 17.5 at 1 year (P < .01). Mortality was 0% at 30 days and 18.4% at 1 year. The average baseline LVEF was 36.1 ± 9.4. Left ventricular function improved to 43.5 ± 12.9 (P <.001) at 30 days and 46.3 ± 11.2 (P = .03) at 1 year. Complications post-TAVR at 30 days included stroke (1.3%) and PPM (11.8%). Patients with D2 AS exhibited higher baseline conduction defects including atrial fibrillation and higher postoperative PPM than those with other subtypes. Conclusions: Patients with D2 AS had significantly improved LVEF and QoL following TAVR at 30 days and 1 year. Postoperative rates of new PPM were higher than other subtypes, while stroke, dialysis, and mortality were lower than expected, supporting the benefit of TAVR in this high-risk group.

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Patients with paradoxical low-flow low-gradient aortic stenosis pose a diagnostic challenge when it comes to assessing the severity of aortic stenosis (AS) noninvasively. We describe 2 patients who underwent exercise cardiac catheterization to augment their cardiac output and assess the severity of AS invasively to allow differentiation of true severe AS from pseudo-severe AS.

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BACKGROUND: 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. METHODS: 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 0.512 mm/mmHg), into 429 patients with preserved and 433 patients with reduced RV/PAc. RESULTS: 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. CONCLUSIONS: 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.

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[This corrects the article DOI: 10.3389/fcvm.2024.1323023.].

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Background: Efficacy of balloon mitral valvuloplasty (BMV) in low gradient severe rheumatic mitral stenosis (MS) is not very well defined. This study was undertaken to evaluate the outcomes of BMV in low gradient severe rheumatic MS. Methods: Severe MS was defined as mitral valve area < 1.5 cm2. Low gradient was defined as mean diastolic trans-mitral gradient (MG) < 10 mmHg and low flow as stroke volume index < 35 ml/m2 on echocardiography. Sixty patients were divided into normal-flow/low-gradient (NFLG) (40) and low-flow/low-gradient (LFLG) (20) groups. Post-BMV parameters were recorded after 72 h and at the end of one year. Results: Mean age was 36.2 ± 6.6 years in NFLG group and 40.6 ± 2.6 years in LFLG group (p < 0.01) and females were 75 % (n = 30) in NFLG group as compared to 60 % (n = 12) in LFLG group. Patients in the LFLG group had higher Wilkins score (p < 0.02) and prevalence of atrial fibrillation (n = 8, 40 %) as compared to NFLG group (n = 7, 17.5 %; p < 0.01). A greater decrease in MG was observed in NFLG group (p < 0.01), whereas increase in MVA was comparable in both the groups (p > 0.05). Ninety percent (n = 36) patients improved in NFLG group in comparison to 70 % (n = 14) in LFLG group (p < 0.01). At the end of one-year, symptomatic improvement persisted in all patients who became asymptomatic post-BMV. Conclusion: Symptomatic improvement following BMV was better seen in NFLG group because of greater decrease in MG in comparison to LFLG group. Results of BMV were suboptimal in LFLG group because of higher sub-valvular obstruction, increased age and higher prevalence of AF.

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Valvular heart disease (VHD) is a significant clinical problem associated with high morbidity and mortality. Although not being the primary imaging modality in VHD, cardiac computed tomography (CCT) provides relevant information about its morphology, function, severity grading, and adverse cardiac remodeling assessment. Aortic valve calcification quantification is necessary for grading severity in cases of low-flow/low-gradient aortic stenosis. Moreover, CCT details significant information necessary for adequate percutaneous treatment planning. CCT may help to detail the etiology of VHD as well as to depict other less frequent causes of valvular disease, such as infective endocarditis, valvular neoplasms, or other cardiac pseudomasses.

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Aesop's fable of the wolf in sheep's clothing encourages us to look beneath the exterior appearance of a situation and evaluate the truth that lies beneath. This concept should be applied when managing older patients with severe aortic stenosis. This population of patients is increasingly being identified as having concomitant cardiac amyloidosis, which is an underrecognized cause of common cardiac conditions. The presence of cardiac amyloidosis negatively affects the outcome of patients with aortic stenosis, these patients undergo transcatheter aortic valve replacement (TAVR) with increasing frequency and have a significantly higher overall mortality rate than patients with aortic stenosis alone. Although left ventricular wall hypertrophy is expected in patients with aortic stenosis, it should not be assumed that this is caused only by aortic stenosis. A suspicion of cardiac amyloidosis should be raised in patients in whom the degree of hypertrophy is disproportionate to the degree of aortic stenosis severity. The remodeling, age, injury, systemic, and electrical (RAISE) score was developed to predict the presence of cardiac amyloidosis in patients with severe aortic stenosis. This article highlights the value of increased clinical suspicion, demonstrates the use of the multiparameter RAISE score in daily clinical practice, and illustrates the scoring system with case studies. In elderly patients being considered for TAVR, systematic testing for cardiac amyloidosis should be considered as part of the preoperative workup.

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OBJECTIVES: A systematic review of the literature was conducted to analyze the current evidence on low-flow, low-gradient severe aortic stenosis. This analysis aimed to differentiate between subgroups of patients with reduced and preserved left ventricular ejection fraction (LVEF). METHODS: After conducting a systematic literature review, 35 observational studies were included. Out of these, 28 were prospective and 7 retrospective. The studies that included a mortality risk stratification of low-flow, low-gradient aortic stenosis (LF- LG AS) with both preserved and reduced LVEF were reviewed. RESULTS: The importance of considering multiple clinical and echocardiographic variables in diagnostic evaluation and therapeutic decision-making was highlighted. CONCLUSIONS: LF- LG AS, in any of its subgroups, is a common and challenging valve lesion. A careful assessment of severity and, in specific scenarios, a thorough reclassification is important. More high-quality studies are required to more precisely define the classification and prognosis of this entity.

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AIM: 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. METHODS AND RESULTS: 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]-ß), 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-ß (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. 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.

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Introduction: Previous analyses have reported the outcomes of transcatheter aortic valve replacement (TAVR) for patients with low-flow, low-gradient (LFLG) aortic stenosis (AS), without stratifying according to the route of access. Differences in mortality rates among access routes have been established for high-gradient (HG) patients and hypothesized to be even more pronounced in LFLG AS patients. This study aims to compare the outcomes of patients with LFLG or HG AS following transfemoral (TF) or transapical (TA) TAVR. Methods: A total of 910 patients, who underwent either TF or TA TAVR with a median follow-up of 2.22 (IQR: 1.22-4.03) years, were included in this multicenter cohort study. In total, 146 patients (16.04%) suffered from LFLG AS. The patients with HG and LFLG AS were stratified according to the route of access and compared statistically. Results: The operative mortality rates of patients with HG and LFLG were found to be comparable following TF access. The operative mortality rate was significantly increased for patients who underwent TA access [odds ratio (OR): 2.91 (1.54-5.48), p = 0.001] and patients with LFLG AS [OR: 2.27 (1.13-4.56), p = 0.02], which could be corroborated in a propensity score-matched subanalysis. The observed increase in the risk of operative mortality demonstrated an additive effect [OR for TA LFLG: 5.45 (2.35-12.62), p < 0.001]. LFLG patients who underwent TA access had significantly higher operative mortality rates (17.78%) compared with TF LFLG (3.96%, p = 0.016) and TA HG patients (6.36%, p = 0.024). Conclusions: HG patients experienced a twofold increase in operative mortality rates following TA compared with TF access, while LFLG patients had a fivefold increase in operative mortality rates. TA TAVR appears suboptimal for patients with LFLG AS. Prospective studies should be conducted to evaluate alternative options in cases where TF is not possible.