Prevalence and Outcomes of Low-Gradient Severe Aortic Stenosis-From the National Echo Database of Australia.
ABSTRACT: Background The prevalence and outcomes of the different subtypes of severe low-gradient aortic stenosis (AS) in routine clinical cardiology practice have not been well characterized. Methods and Results Data were derived from the National Echocardiography Database of Australia. Of 192 060 adults (aged 62.8±17.8 [mean±SD] years) with native aortic valve profiling between 2000 and 2019, 12 013 (6.3%) had severe AS. Of these, 5601 patients (47%) had high-gradient and 6412 patients (53%) had low-gradient severe AS. The stroke volume index was documented in 2741 (42.7%) patients with low gradient; 1750 patients (64%) with low flow, low gradient (LFLG); and 991 patients with normal flow, low gradient. Of the patients with LFLG, 1570 (89.7%) had left ventricular ejection fraction recorded; 959 (61%) had paradoxical LFLG (preserved left ventricular ejection fraction), and 611 (39%) had classical LFLG (reduced left ventricular ejection fraction). All-cause and cardiovascular-related mortality were assessed in the 8162 patients with classifiable severe AS subtype during a mean±SD follow-up of 88±45 months. Actual 1-year and 5-year all-cause mortality rates varied across these groups and were 15.8% and 49.2% among patients with high-gradient severe AS, 11.6% and 53.6% in patients with normal-flow, low-gradient severe AS, 16.9% and 58.8% in patients with paradoxical LFLG severe AS, and 30.5% and 72.9% in patients with classical LFLG severe AS. Compared with patients with high-gradient severe AS, the 5-year age-adjusted and sex-adjusted mortality risk hazard ratios were 0.94 (95% CI, 0.85-1.03) in patients with normal-flow, low-gradient severe AS; 1.01 (95% CI, 0.92-1.12) in patients with paradoxical LFLG severe AS; and 1.65 (95% CI, 1.48-1.84) in patients with classical LFLG severe AS. Conclusions Approximately half of those patients with echocardiographic features of severe AS in routine clinical practice have low-gradient hemodynamics, which is associated with long-term mortality comparable with or worse than high-gradient severe AS. The poorest survival was associated with classical LFLG severe AS.
Project description:An important proportion of patients with aortic stenosis (AS) have a 'low-gradient' AS, i.e. a small aortic valve area (AVA <1.0 cm(2)) consistent with severe AS but a low mean transvalvular gradient (<40 mmHg) consistent with non-severe AS. The management of this subset of patients is particularly challenging because the AVA-gradient discrepancy raises uncertainty about the actual stenosis severity and thus about the indication for aortic valve replacement (AVR) if the patient has symptoms and/or left ventricular (LV) systolic dysfunction. The most frequent cause of low-gradient (LG) AS is the presence of a low LV outflow state, which may occur with reduced left ventricular ejection fraction (LVEF), i.e. classical low-flow, low-gradient (LF-LG), or preserved LVEF, i.e. paradoxical LF-LG. Furthermore, a substantial proportion of patients with AS may have a normal-flow, low-gradient (NF-LG) AS: i.e. a small AVA-low-gradient combination but with a normal flow. One of the most important clinical challenges in these three categories of patients with LG AS (classical LF-LG, paradoxical LF-LG, and NF-LG) is to differentiate a true-severe AS that generally benefits from AVR vs. a pseudo-severe AS that should be managed conservatively. A low-dose dobutamine stress echocardiography may be used for this purpose in patients with classical LF-LG AS, whereas aortic valve calcium scoring by multi-detector computed tomography is the preferred modality in those with paradoxical LF-LG or NF-LG AS. Although patients with LF-LG severe AS have worse outcomes than those with high-gradient AS following AVR, they nonetheless display an important survival benefit with this intervention. Some studies suggest that transcatheter AVR may be superior to surgical AVR in patients with LF-LG AS.
Project description:Background No randomized comparison of early (ie, ?3 months) aortic valve replacement (AVR) versus conservative management or of transcatheter AVR (TAVR) versus surgical AVR has been conducted in patients with low-flow, low-gradient (LFLG) aortic stenosis (AS). Methods and Results A total of 481 consecutive patients (75±10 years; 71% men) with LFLG AS (aortic valve area ?0.6 cm<sup>2</sup>/m<sup>2</sup> and mean gradient <40 mm Hg), 72% with classic LFLG and 28% with paradoxical LFLG, were prospectively recruited in the multicenter TOPAS (True or Pseudo Severe Aortic Stenosis) study. True-severe AS or pseudo-severe AS was adjudicated by flow-independent criteria. During follow-up (median [IQR] 36 [11-60] months), 220 patients died. Using inverse probability of treatment weighting to address the bias of nonrandom treatment assignment, early AVR (n=272) was associated with a major overall survival benefit (hazard ratio [HR], 0.34 [95% CI, 0.24-0.50]; <i>P</i><0.001). This benefit was observed in patients with true-severe AS but also with pseudo-severe AS (HR, 0.38 [95% CI, 0.18-0.81]; <i>P</i>=0.01), and in classic (HR, 0.33 [95% CI, 0.22-0.49]; <i>P</i><0.001) and paradoxical LFLG AS (HR, 0.42 [95% CI, 0.20-0.92]; <i>P</i>=0.03). Compared with conservative management in the conventional multivariate model, trans femoral TAVR was associated with the best survival (HR, 0.23 [95% CI, 0.12-0.43]; <i>P</i><0.001), followed by surgical AVR (HR, 0.36 [95% CI, 0.23-0.56]; <i>P</i><0.001) and alternative-access TAVR (HR, 0.51 [95% CI, 0.31-0.82]; <i>P</i>=0.007). In the inverse probability of treatment weighting model, trans femoral TAVR appeared to be superior to surgical AVR (HR [95% CI] 0.28 [0.11-0.72]; <i>P</i>=0.008) with regard to survival. Conclusions In this large prospective observational study of LFLG AS, early AVR appeared to confer a major survival benefit in both classic and paradoxical LFLG AS. This benefit seems to extend to the subgroup with pseudo-severe AS. Our findings suggest that TAVR using femoral access might be the best strategy in these patients. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01835028.
Project description:Importance:In low-flow, low-gradient aortic stenosis (LFLG AS), the severity of left ventricular dysfunction remains a key factor in the evaluation of aortic valve replacement. Objective:To evaluate the clinical outcomes and changes in left ventricular ejection fraction (LVEF) after transcatheter aortic valve replacement (TAVR) in patients with LFLG AS and severe left ventricular dysfunction. Design, Setting, and Participants:This multicenter registry is a substudy of the True or Pseudo-Severe Aortic Stenosis-TAVI registry that included patients with classic LFLG AS, defined as a mean transvalvular gradient less than 35 mm Hg, an effective orifice area less than 1.0 cm2, and an LVEF of 40% or less. Patients were divided in groups with very low (<30%) LVEF and low (30%-40%) LVEF. Dobutamine stress echocardiography (DSE) was performed before TAVR in a subset with very low LVEF, and presence of contractile reserve was defined as an increase of 20% or more in stroke volume. Clinical outcomes were assessed at 1 and 12 months and yearly thereafter, and echocardiography was performed at 1-year follow-up. Retrospective data were collected from 2007 to 2013 and prospective data from January 2013 to March 2018. Data were analyzed from March to October 2018. Exposures:Transcatheter aortic valve replacement in patients with LFLG AS. Main Outcomes and Measures:Changes in LVEF over time; periprocedural and late mortality. Results:A total of 293 patients were included, including 128 (43.7%) with very low LVEF and 165 with low LVEF (56.3%). Their mean (SD) age was 80 (7) years, and most (214 [73.0%]) were men. The mean (SD) LVEF in the very low LVEF group was 22% (5%), compared with 37% (7%) in the low LVEF group (P?<?.001). There were no differences between groups in rates of periprocedural mortality and late mortality (median [interquartile range], 23 [6-38] months). Patients with very low LVEF displayed a greater increase in LVEF at the 1-year follow-up examination (mean absolute increase, 11.9% [95% CI, 8.8%-15.1%]), than the low LVEF group (3.6% [95% CI, 1.1%-6.1%]; P?<?.001). In 92 patients with very low LVEF who had preprocedural DSE, results showed a lack of contractile reserve in 45 (49%), but this had no effect on clinical outcomes or changes in LVEF over time. Conclusions and Relevance:In patients with LFLG AS and severe left ventricular dysfunction, TAVR was associated with similar clinical outcomes as in counterparts with milder left ventricular dysfunction. The TAVR procedure was associated with a significant increase in LVEF, irrespective of contractile reserve. These results support TAVR for LFLG AS, irrespective of the severity of left ventricular dysfunction and DSE results.
Project description:The survival benefits of aortic valve replacement (AVR) in the different flow-gradient states of severe aortic stenosis (AS) is not known. A comprehensive search in PubMed/MEDLINE, Embase, Cochrane Library, CNKI and OpenGrey were conducted to identify studies that investigated the prognosis of severe AS (effective orifice area ≤1.0 cm<sup>2</sup>) and left ventricular ejection fraction ≥50%. Severe AS was stratified by mean pressure gradient [threshold of 40 mmHg; high-gradient (HG) and low-gradient (LG)] and stroke volume index [threshold of 35 ml/m<sup>2</sup>; normal-flow (NL) and low-flow (LF)]. Network meta-analysis was conducted to assess all-cause mortality among each AS sub-type with rate ratio (RR) reported. The effects of AVR on prognosis were examined using network meta-regression. In the pooled analysis (15 studies and 9,737 patients), LF states (both HG and LG) were associated with increased mortality rate (LFLG: RR 1.88; 95% CI: 1.43-2.46; LFHG: RR: 1.77; 95% CI: 1.16-2.70) compared to moderate AS; and NF states in both HG and LG had similar prognosis as moderate AS (NFLG: RR 1.11; 95% CI: 0.81-1.53; NFHG: RR 1.16; 95% CI: 0.82-1.64). AVR conferred different survival benefits: it was most effective in NFHG (RR <sub>with AVR</sub> /RR <sub>without AVR</sub> : 0.43; 95% CI: 0.22-0.82) and least in LFLG (RR <sub>with AVR</sub> /RR <sub>without AVR</sub> : 1.19; 95% CI: 0.74-1.94).
Project description:Titin-isoform expression, titin phosphorylation, and myocardial fibrosis were studied in 30 patients with severe symptomatic aortic stenosis (AS). Patients were grouped into "classical" high-gradient, normal-flow AS with preserved ejection fraction (EF); "paradoxical" low-flow, low-gradient AS with preserved EF; and AS with reduced EF. Nonfailing donor hearts served as controls. AS was associated with increased fibrosis, titin-isoform switch toward compliant N2BA, and both total and site-specific titin hypophosphorylation compared with control hearts. All AS subtypes revealed titin and matrix alterations. The extent of myocardial remodeling in "paradoxical" AS was no less severe than in other AS subtypes, thus explaining the unfavorable prognosis.
Project description:<h4>Background</h4>Myocardial oxygen consumption (MVO<sub>2</sub>) and its coupling to contractile work are fundamentals of cardiac function and may be involved causally in the transition from compensated left ventricular hypertrophy to failure. Nevertheless, these processes have not been studied previously in patients with aortic valve stenosis (AS).<h4>Methods and results</h4>Participants underwent <sup>11</sup>C-acetate positron emission tomography, cardiovascular magnetic resonance, and echocardiography to measure MVO<sub>2</sub> and myocardial external efficiency (MEE) defined as the ratio of left ventricular stroke work and the energy equivalent of MVO<sub>2</sub>. We studied 10 healthy controls (group A), 37 asymptomatic AS patients with left ventricular ejection fraction ?50% (group B), 12 symptomatic AS patients with left ventricular ejection fraction ?50% (group C), and 9 symptomatic AS patients with left ventricular ejection fraction <50% (group D). MVO<sub>2</sub> did not differ among groups A, B, C, and D (0.105±0.02, 0.117±0.024, 0.129±0.032, and 0.104±0.026 mL/min per gram, respectively; P=0.07), whereas MEE was reduced in group D (21.0±1.6%, 22.3±3.3%, 22.1±4.2%, and 17.3±4.7%, respectively; P<0.05). Similarly, patients with global longitudinal strain greater than -12% and paradoxical low-flow, low-gradient AS had impaired MEE (P<0.05 versus controls). The ability to discriminate between symptomatic and asymptomatic patients was superior for global longitudinal strain compared with MVO<sub>2</sub> and MEE (area under the curve 0.98, 0.48, and 0.61, respectively; P<0.05).<h4>Conclusions</h4>AS patients display a persistent ability to maintain normal MVO<sub>2</sub> and MEE (ie, the ability to convert energy into stroke work); however, patients with left ventricular ejection fraction <50%; global longitudinal strain greater than -12%; or paradoxical low-flow, low-gradient AS demonstrate reduced MEE. These findings suggest that mitochondrial uncoupling contributes to the dismal prognosis in patients with reduced contractile function or paradoxical low-flow, low-gradient AS.
Project description:<h4>Objective</h4>Patients with low-flow, low-gradient aortic stenosis (LFLG AS) and reduced left ventricular ejection fraction (LVEF) are known to suffer from poor prognosis after transcatheter aortic valve implantation (TAVI). This study aimed to develop a simple score system for risk prediction in this vulnerable subset of patients.<h4>Methods</h4>All patients with LFLG AS with reduced EF and sufficient CT data for aortic valve calcification (AVC) quantification, who underwent TAVI at five German centres, were retrospectively included. The Risk prEdiction in patients with Low Ejection Fraction low gradient aortic stenosis undergoing TAVI (RELiEF TAVI) score was developed based on multivariable Cox regression for all-cause mortality.<h4>Results</h4>Among all included patients (n=718), RELiEF TAVI score variables were defined as independent predictors of mortality: male sex (HR 1.34 (1.06, 1.68), p=0.013), underweight (HR 3.10 (1.50, 6.40), p=0.0022), chronic obstructive pulmonary disease (HR 1.55 (1.21, 1.99), p=0.001), pulmonary hypertension (HR 1.51 (1.17, 1.94), p=0.0015), atrial fibrillation (HR 1.28 (1.03, 1.60), p=0.028), stroke volume index (HR 0.96 (0.95, 0.98), p<0.001), non-transfemoral access (HR 1.36 (1.05, 1.76), p=0.021) and low AVC density (HR 1.44 (1.15, 1.79), p=0.0012). A score system was developed ranging from 0 to 12 points (risk of 1-year mortality: 13%-99%). Kaplan-Meier analysis for low (0-1 points), moderate (2-4 points) and high RELiEF TAVI score (>4 points) demonstrated rates of 18.0%, 29.0% and 46.1% (p<0.001) for all-cause mortality and 23.8%, 35.9% and 53.4% (p<0.001) for the combined endpoint of all-cause mortality or heart failure rehospitalisation after 1 year, respectively.<h4>Conclusions</h4>The RELiEF TAVI score is based on simple clinical, echocardiographic and CT parameters and might serve as a helpful tool for risk prediction in patients with LFLG AS and reduced LVEF scheduled for TAVI.
Project description:An 86-year-old man with unremarkable clinical history complaining of asthenia and dyspnea was diagnosed with low-flow low-gradient aortic stenosis [LFLG-AS; left ventricular ejection fraction (LVEF) 40% and transaortic mean gradient 37 mmHg, increasing to 52% and 55 mmHg after dobutamine infusion]. The patient underwent transcatheter aortic valve implantation (TAVI; Edwards CENTERA™ 29, Irvine, CA, USA). The procedure and the following hospital stay were free from complications, with no changes on electrocardiography (ECG). Six months later, few syncopal episodes occurred. No signs of orthostatic hypotension or neurologic disorders were present. Echocardiography showed normal functioning of the prosthetic valve and recovery of LV systolic function (LVEF 55%). Baseline ECG and 24-h Holter monitoring were unremarkable. An implantable loop recorder (ILR) was implanted to verify the occurrence of paroxysmal conduction disturbances. One month later, during a syncopal episode, ILR interrogation showed a complete atrioventricular (AV) block. Therefore, a dual chamber, single lead pacemaker was implanted. We are providing the first report of complete AV block occurring months after TAVI, possibly because of reverse LV remodeling following TAVI, with ensuing relative oversizing of the prosthetic valve. This possibility should be considered in patients with syncope not otherwise explained, and previous TAVI, especially in cases of LFLG-AS. <<b>Learning objective:</b> Complete atrioventricular block can occur even months after transcatheter aortic valve implantation (TAVI), possibly because of left ventricular reverse remodeling following valve replacement, with ensuing relative valve oversizing. This possibility should be considered in patients with syncope not otherwise explained, and previous TAVI, especially in cases of low flow low gradient aortic stenosis. Loop recorder implantation should be considered in this group of patients.>.
Project description:<h4>Objectives</h4>The association between extracellular volume (ECV) measured by computed tomography angiography (CTA) and clinical outcomes was evaluated in low-flow low-gradient (LFLG) aortic stenosis (AS) patients undergoing transcatheter aortic valve replacement (TAVR).<h4>Background</h4>Patients with LFLG AS comprise a high-risk group with respect to clinical outcomes. Although ECV, a marker of myocardial fibrosis, is traditionally measured with cardiac magnetic resonance, it can also be measured using cardiac CTA. The authors hypothesized that in LFLG AS, increased ECV may be associated with adverse clinical outcomes.<h4>Methods</h4>In 150 LFLG patients with AS who underwent TAVR, ECV was quantified using pre-TAVR CTA. Echocardiographic and clinical information including all-cause death and heart failure rehospitalization (HFH) was obtained from electronic medical records. A Cox proportional hazards model was used to evaluate the association between ECV and death+HFH.<h4>Results</h4>During a median follow-up of 13.9 months (range 0.07 to 28.9 months), there were 31 death+HFH events (21%). Patients who experienced death+HFH had a greater median Society of Thoracic Surgery score (9.9 vs. 4.7; p < 0.01), lower left ventricular ejection fraction (42.3 ± 20.2% vs. 52.7 ± 17.2%; p < 0.01), lower mean transvalvular gradient (24.9 ± 8.9 mm Hg vs. 28.1 ± 7.3 mm Hg; p = 0.04) and increased mean ECV (35.5 ± 9.6% vs. 29.9 ± 8.2%; p < 0.01) compared with patients who did not experience death+HFH. In a multivariable Cox proportional hazards model, increase in ECV was associated with increase in death+HFH, (hazard ratio per 1% increase: 1.04, 95% confidence interval: 1.01 to 1.09; p < 0.01).<h4>Conclusions</h4>In patients with LFLG AS, CTA measured increase in ECV is associated with increased risk of adverse clinical outcomes post-TAVR and may thus serve as a useful noninvasive marker for prognostication.
Project description:<h4>Background</h4>Impaired left ventricular (LV) ejection fraction is a common finding in patients with aortic stenosis and serves as a predictor of morbidity and mortality after transcatheter aortic valve replacement. However, conflicting data on the most accurate measure for LV function exist. We wanted to examine the impact of LV ejection fraction, mean pressure gradient, and stroke volume index on the outcome of patients treated by transcatheter aortic valve replacement.<h4>Methods and results</h4>Patients treated by transcatheter aortic valve replacement were primarily separated into normal flow (NF; stroke volume index >35 mL/m<sup>2</sup>) and low flow (LF; stroke volume index ?35 mL/m<sup>2</sup>). Afterwards, patients were divided into 5 groups: "NF-high gradient," "NF-low gradient" (NF-LG), "LF-high gradient," "paradoxical LF-LG," and "classic LF-LG." The 3-year mortality was the primary end point. Of 1600 patients, 789 (49.3%) were diagnosed as having LF, which was characterized by a higher 30-day (<i>P</i>=0.041) and 3-year (<i>P</i><0.001) mortality. LF was an independent predictor of all-cause (hazard ratio, 1.29; 95% confidence interval, 1.03-1.62; <i>P</i>=0.03) and cardiovascular (hazard ratio, 1.37; 95% confidence interval, 1.06-1.77; <i>P</i>=0.016) mortality. Neither mean pressure gradient nor LV ejection fraction was an independent predictor of mortality. Patients with paradoxical LF-LG (35.0%), classic LF-LG (35.1%) and LF-high gradient (38.1%) had higher all-cause mortality at 3 years compared with NF-high gradient (24.8%) and NF-LG (27.9%) (<i>P</i>=0.001). However, surviving patients showed a similar improvement in symptoms regardless of aortic stenosis entity.<h4>Conclusions</h4>LF is a common finding within the aortic stenosis population and, in contrast to LV ejection fraction or mean pressure gradient, an independent predictor of all-cause and cardiovascular mortality. Despite increased long-term mortality, high procedural success and excellent functional improvement support transcatheter aortic valve replacement in patients with LF severe aortic stenosis.