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Multicenter Prospective Study of Low-Flow Low-Gradient Aortic Stenosis (TOPAS Study)

Overview

About this study

Low-flow, low-gradient (LF-LG) aortic stenosis (AS) may occur with depressed (i.e. Classical LF; CLF) or preserved (i.e. Paradoxical LF; PLF) LV ejection fraction (LVEF) and both situations are amongst the most challenging encountered in patients with valvular heart disease. Although, CLF-LG AS is recognized has an important clinical entity, current ACC/AHA-ESC guidelines however do not provide precise recommendations for clinical management of these patients . PLF-LG AS is a new entity recently described by our group, which is characterized by more pronounced LV concentric remodeling with smaller LV cavity size and a restrictive physiology leading to impaired LV filling, altered myocardial function, and a low-flow state. Up to recently, this entity was often misdiagnosed, leading to underestimation of AS severity and inappropriate delays for aortic valve replacement surgery (SAVR). The two main challenges in patients with CLF- or PLF- LG AS are to distinguish between a true-severe (TS) versus a pseudo-severe (PS) stenosis and to accurately quantify the extent of myocardial impairment. Unfortunately, the traditional resting and stress echocardiographic parameters currently used to assess the severity of valvular and myocardial dysfunction in patients with LF-LG AS are far from being optimal, and as a consequence, quantification of disease severity and therapeutic management may not be appropriate in a substantial proportion of these patients.

THE GENERAL OBJECTIVES of the TOPAS study are to develop and validate new parameters and biomarkers to improve the assessment of stenosis severity and myocardial impairment, the risk-stratification, and the clinical decision making in patients with LF-LG AS and to assess the impact of the different therapeutic strategies on patient outcomes.

Participation eligibility

Participant eligibility includes age, gender, type and stage of disease, and previous treatments or health concerns. Guidelines differ from study to study, and identify who can or cannot participate. There is no guarantee that every individual who qualifies and wants to participate in a trial will be enrolled. Contact the study team to discuss study eligibility and potential participation.

Inclusion Criteria:

  • LVEF≤ 40%
  • Indexed aortic valve area (AVA) ≤ 0.6 cm²/m²
  • Mean transvalvular gradient < 40 mmHg

Exclusion criteria:

  • Pregnant or lactating women
  • advanced renal failure
  • tumor with metastasis

Participating Mayo Clinic locations

Study statuses change often. Please contact the study team for the most up-to-date information regarding possible participation.

Mayo Clinic Location Status

Rochester, Minn.

Mayo Clinic principal investigator

Maurice Sarano, M.D.

Closed for enrollment

More information

Publications

  • Controversial data exist on clinical outcomes of patients with paradoxical low-flow, low-gradient aortic stenosis (PLF-LG-AS) undergoing valve replacement. The objective of this study was to determine the clinical outcomes and treatment futility in patients with paradoxical low-flow (PLF), low-gradient (LG) severe aortic stenosis (AS) undergoing transcatheter aortic valve implantation (TAVI). A total of 493 patients with severe symptomatic AS and preserved ejection fraction (>50%) undergoing TAVI were included. Patients were divided in two groups: high gradient AS group (HG-AS; mean gradient ≥40 mm Hg and stroke volume index >35 ml/m, n = 396); and PLF, LG AS group (PLF-LG-AS; mean AV gradient <40 mm Hg and indexed stroke volume ≤35 ml/m, n = 97). The primary endpoint was treatment futility defined as death or poor functional status (New York Heart Association class III and/or IV) at 6-month follow-up. There were no differences in mortality between groups (PLF-LG-AS: 5%, HG: 8%; adjusted odds ratio (OR): 0.85, 95% confidence interval (CI):0.29 to 2.46), but PLF-LG-AS patients remained more frequently in New York Heart Association class III to IV (20% vs 8% in the HG group, adjusted OR: 2.46, 95% CI:1.19 to 5.07). TAVI treatment futility was more frequent in the PLF-LG-AS group (24% vs 14%, adjusted OR: 1.90 [1.01 to 3.57]), and patients with PLF-LG-AS exhibited a higher rate of rehospitalization for cardiovascular causes (9% vs 5%, adjusted OR: 2.95, 95% CI:1.08 to 8.09). Previous myocardial infarction and chronic obstructive pulmonary disease were associated with treatment futility (p< 0.03 for both). In conclusion, TAVI was a futile treatment in one fourth of patients with PLF-LG-AS. These results underscore the complexity and need for improving the clinical decision-making process and management of patients with PLF-LG-AS. Read More on PubMed
  • About 60% of patients with paradoxical low-flow, low-gradient (PLF-LG) aortic stenosis (AS) have a severe disease that justifies aortic valve replacement (AVR). The first step in patients with symptomatic PLF AS should be to rule out measurement errors and treat hypertension. The second step is to distinguish pseudo-severe from true severe AS (TSAS). The third step is to select the optimal treatment modality at the right time. Regarding the second step, projected aortic valve area calculated using stress echocardiography is superior to traditional severity criteria (AVA < 1.0 cm and mean gradient ≥ 40 mmHg) to unmask TSAS and predict outcomes. Aortic valve calcification score quantitated by computed tomography is helpful to identify TSAS by applying thresholds of 2000 and 1200 AU, respectively, for men and women. This modality should be considered, particularly if stress echocardiography is either not feasible or inconclusive. Once AS severity is confirmed, a risk stratification based on symptomatic status and the importance of left ventricular (LV) systolic impairment will guide therapeutic decision. Symptomatic assessment should not solely rely on patient-reported symptom status, but rather include an objective exercise test. The presence of symptomatic PLF-LG TSAS is a class IIa indication for AVR in the guidelines. In asymptomatic patients, a markedly reduced stroke volume, the presence of myocardial fibrosis by cardiac magnetic resonance imaging, a poor longitudinal LV function as assessed by speckle tracking echocardiography, and/or a moderate to severe LV diastolic dysfunction are predictors of poor outcome in PLF-LG patients and may indicate the need of early AVR. The type of AVR should be discussed within a multidisciplinary team, bearing in mind that transcatheter AVR (TAVR) is superior to medical treatment in inoperable patients. Furthermore, TAVR may be a useful alternative to surgical AVR (SAVR) in high-risk patients. Nevertheless, the potential benefits of TAVR, including the lower risk of severe patient-prosthesis mismatch, should be weighed against the risk of paravalvular regurgitation, which is likely poorly tolerated by patients with PLF-LG who often harbor a small and non-compliant LV cavity. Read More on PubMed
  • Few data exist on patients with low-flow, low-gradient aortic stenosis (LFLG-AS) undergoing transcatheter aortic valve replacement (TAVR). Also, very scarce data exist on the usefulness of dobutamine stress echocardiography (DSE) before TAVR in these patients. Read More on PubMed
  • In the American College of Cardiology/American Heart Association guidelines, patients are considered to have true-severe stenosis when the mean gradient (MG) is ≥40 mm Hg with an aortic valve area (AVA) ≤1 cm during dobutamine stress echocardiography (DSE). However, these criteria have not been previously validated. Read More on PubMed
  • Left ventricular global longitudinal strain (LVLS) is a powerful predictor of outcome in patients with low-flow, low-gradient aortic stenosis (LF-LG AS) and low LV ejection fraction (LVEF). However, the impact of right ventricular (RV) function on the outcome of these patients remains unknown. Read More on PubMed
  • Low mean transvalvular gradient (<40 mm Hg) and small aortic valve area (<1.0 cm(2)) in patients with aortic stenosis (AS) and preserved left ventricular ejection fraction raises uncertainty about the actual severity of the stenosis and survival benefit of aortic valve replacement (AVR). Read More on PubMed
  • Low flow (LF), defined as stroke volume index (SVi) <35 mL/m(2), prior to the procedure has been recently identified as a powerful independent predictor of early and late mortality in patients undergoing transcatheter aortic valve replacement (TAVR). The objectives of this study were to determine the evolution of SVi following TAVR and to assess the determinants and impact on mortality of early postprocedural SVi (EP-SVi). Read More on PubMed
  • This study sought to examine the impact of tricuspid regurgitation (TR) on mortality in patients with low-flow, low-gradient (LF-LG) aortic stenosis (AS) and reduced left ventricular ejection fraction (LVEF). Read More on PubMed
  • The objective of this study was to examine the impact of left ventricular (LV) global longitudinal strain (GLS) measured at rest and at dobutamine stress echocardiography on the outcome of patients with low LV ejection fraction and low-gradient aortic stenosis. Read More on PubMed
  • Low flow (LF) can occur with reduced (classic) or preserved (paradoxical) left ventricular ejection fraction (LVEF). Read More on PubMed
  • We reported that patients with small aortic valve area (AVA) and low flow despite preserved left ventricular ejection fraction (LVEF), i.e. 'paradoxical' low flow (PLF), have worse outcomes compared with patients with normal flow (NF), although they generally have a lower mean gradient (MG). The aortic valve weight (AVW) excised at the time of valve replacement is a flow-independent marker of stenosis severity. The objective of this study was to compare the AVW of patients with PLF and MG<40 mmHg with the AVW of patients with NF and MG≥40 mmHg. Read More on PubMed
  • Patients with severe aortic stenosis (AS) and paradoxical low flow (PLF) have worse outcome compared with those with normal flow. Furthermore, prosthesis-patient mismatch (PPM) after aortic valve replacement is a predictor of reduced survival. However, the prevalence and prognostic impact of PPM in patients with PLF-AS are unknown. We aimed to analyze the prevalence and long-term survival of PPM in patients with PLF-AS. Read More on PubMed
  • The clinical relevance and management of paradoxical low-flow, low-gradient aortic stenosis (LFLG-AS) with preserved left ventricular ejection fraction remain debated. The aim of this study is to determine the features and outcome of LFLG-AS assessed using cardiac catheterization. Read More on PubMed
  • This study sought to assess the impact of baseline left ventricular (LV) outflow, LV ejection fraction (LVEF), and transvalvular gradient on outcomes following transcatheter aortic valve replacement (TAVR) in patients with severe aortic stenosis (AS). Read More on PubMed
  • The objective of this study was to examine the value of stress-echocardiography in patients with paradoxical low-flow, low-gradient (PLFLG) aortic stenosis (AS). The projected aortic valve area (AVAProj) at a normal flow rate was calculated in 55 patients with PLFLG AS. In the subset of patients (n = 13) who underwent an aortic valve replacement within 3 months after stress echocardiography, AVA(Proj) correlated better with the valve weight compared to traditional resting and stress echocardiographic parameters of AS severity (AVA(Proj): r = -0.78 vs. other parameters: r = 0.46 to 0.56). In the whole group (N = 55), 18 (33%) patients had an AVA(Proj) >1.0 cm(2), being consistent with the presence of pseudo severe AS. The AVA(Proj) was also superior to traditional parameters of stenosis severity for predicting outcomes (hazard ratio: 1.32/0.1 cm(2) decrease in AVA(Proj)). In patients with PLFLG AS, the measurement of AVA(proj) derived from stress echocardiography is helpful to determine the actual severity of the stenosis and predict risk of adverse events. Read More on PubMed
  • Low-flow, low-gradient (LF-LG) aortic stenosis (AS) may occur with depressed or preserved left ventricular ejection fraction (LVEF), and both situations are among the most challenging encountered in patients with valvular heart disease. In both cases, the decrease in gradient relative to AS severity is due to a reduction in transvalvular flow. The main challenge in patients with depressed LVEF is to distinguish between true severe versus pseudosevere stenosis and to accurately assess the severity of myocardial impairment. Paradoxical LF-LG severe AS despite a normal LVEF is a recently described entity that is characterized by pronounced LV concentric remodeling, small LV cavity size, and a restrictive physiology leading to impaired LV filling, altered myocardial function, and worse prognosis. Until recently, this entity was often misdiagnosed, thereby causing underestimation of AS severity and inappropriate delays for surgery. Hence, the main challenge in these patients is proper diagnosis, often requiring diagnostic tests other than Doppler echocardiography. The present paper proposes to review the diagnostic and therapeutic management specificities of LF-LG AS with and without depressed LV function. Read More on PubMed
  • "Degenerative" or calcific aortic stenosis is a complex, multifaceted, systemic disease that is not solely limited to the aortic valve but also includes reduced arterial compliance as well as alterations of left ventricular geometry and function. This particular nature of the disease underscores the need for a more comprehensive evaluation of disease severity going beyond the standard parameters routinely used to assess stenosis severity (i.e., peak jet velocity, pressure gradients, valve effective orifice area) or left ventricle function (i.e., left ventricular ejection fraction). The present paper thus proposes to review newer approaches to improve the quantification of disease severity taking into account the interrelation between the different valvular, arterial, and ventricular variables that may be responsible for the appearance of symptoms and/or poorer prognosis in patients with aortic stenosis. Read More on PubMed
  • It has been previously demonstrated that a new index of aortic stenosis (AS) severity derived from dobutamine stress echocardiography (DSE), the projected aortic valve area (AVA) at a normal transvalvular flow rate (AVA(proj)), is superior to traditional Doppler echocardiographic indices to discriminate true severe from pseudosevere low-gradient AS. The objectives of this study were to prospectively validate the diagnostic and prognostic value of AVA(proj) in a large series of patients and to propose a new clinically applicable simplified method to estimate AVA(proj). Read More on PubMed
  • Paradoxical low flow, low gradient, severe aortic stenosis (AS) despite preserved ejection fraction is a recently described clinical entity whereby patients with severe AS on the basis of aortic valve area have a lower than expected gradient in relation to generally accepted values. This mode of presentation of severe AS is relatively frequent (up to 35% of cases) and such patients have a cluster of findings, indicating that they are at a more advanced stage of their disease and have a poorer prognosis if treated medically rather than surgically. Yet, a majority of these patients do not undergo surgery likely due to the fact that the reduced gradient is conducive to an underestimation of the severity of the disease and/or of symptoms. The purpose of this article is to review and further analyse the distinguishing characteristics of this entity and to present its implications with regards to currently accepted guidelines for AS severity. Read More on PubMed
  • Exercise testing has an established role in the evaluation of patients with valvular heart disease and can aid clinical decision making. Because symptoms may develop slowly and indolently in chronic valve diseases and are often not recognized by patients and their physicians, the symptomatic, blood pressure, and electrocardiographic responses to exercise can help identify patients who would benefit from early valve repair or replacement. In addition, stress echocardiography has emerged as an important component of stress testing in patients with valvular heart disease, with relevant established and potential applications. Stress echocardiography has the advantages of its wide availability, low cost, and versatility for the assessment of disease severity. The versatile applications of stress echocardiography can be tailored to the individual patient with aortic or mitral valve disease, both before and after valve replacement or repair. Hence, exercise-induced changes in valve hemodynamics, ventricular function, and pulmonary artery pressure, together with exercise capacity and symptomatic responses to exercise, provide the clinician with diagnostic and prognostic information that can contribute to subsequent clinical decisions. Nevertheless, there is a lack of convincing evidence that the results of stress echocardiography lead to clinical decisions that result in better outcomes, and therefore large-scale prospective randomized studies focusing on patient outcomes are needed in the future. Read More on PubMed
  • This study was designed to examine the prognostic value of valvuloarterial impedance (Z(va)) in patients with aortic stenosis (AS). Read More on PubMed
  • This study was designed to evaluate the effect of valve prosthesis-patient mismatch (PPM) on late survival after aortic valve replacement (AVR) and to determine if this effect is modulated by patient age, body mass index (BMI), and pre-operative left ventricular (LV) function. Read More on PubMed
  • Recent studies and current clinical observations suggest that some patients with severe aortic stenosis on the basis of aortic valve area may paradoxically have a relatively low gradient despite the presence of a preserved left ventricular (LV) ejection fraction. The objective of the present study was to document the prevalence, potential mechanisms, and clinical relevance of this phenomenon. Read More on PubMed
  • The prosthesis used for aortic valve replacement (AVR) can be too small in relation to body size, thus causing valve prosthesis-patient mismatch (PPM) and abnormally high transvalvular pressure gradients. This study examined if there is a relation between PPM and short-term mortality after operation. Read More on PubMed
  • Measuring precise antifungal levels in the cornea with broth-dilution bioassays is difficult, as standard techniques involving visual determination of endpoints are hindered by corneal debris. To increase the precision of the measurement, we modified the sample preparation for bioassay of rabbit corneas treated with subconjunctival amphotericin B. Endpoint determination and variance were compared for a freshly thawed corneal suspension and the supernatant after 24 h equilibration; bioassay of the corneal suspension after 24 h equilibration served as an additional control. All endpoints were read visually in a masked fashion and were verified by culture. The three methods gave comparable endpoint values with equivalent degrees of variance. Amphotericin B levels were consistent by both visual and culture determination; however, endpoints were clearly visible and easier to read for the supernatant. Visual determination of the endpoints for the supernatant following 24 h equilibration simplified and ensured the precision of the bioassay technique. Read More on PubMed

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