Paradoxical low-flow, low-gradient aortic stenosis despite preserved left ventricular ejection fraction: new insights from weights of operatively excised aortic valves.

AIMS: 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. METHODS AND RESULTS: We recruited 250 consecutive patients undergoing valve replacement (Cohort A) for severe stenosis. Among them, 33 (13%) were in PLF [LVEF > 50% but stroke volume index (SVi) ≤ 35 mL/m(2)] with MG < 40 mmHg (PLF-LG group) and 105 (42%) were in NF (LVEF > 50% and SVi > 35 mL/m(2)) with MG ≥ 40 mmHg (NF-HG group). Despite a much lower MG (29 ± 7 vs. 53 ± 10 mmHg; P < 0.0001), patients in the PLF-LG group had a similar AVA (0.73 ± 0.12 vs. 0.69 ± 0.13; P = 0.19) compared with those in the NF-HG group. The AVW [median (interquartile): 1.90 (1.63-2.50) vs. 2.60 (1.66-3.32)] and prevalence of bicuspid phenotype (15 vs. 42%) were lower in the PLF-LG group than in the NF-HG group. However, AVWs analysed separately in the tricuspid and bicuspid valves were similar in both groups [tricuspid valves: 1.80 (1.63-2.50) vs. 2.30 (1.58-3.00) g; P = 0.26 and bicuspid valves: 2.72 (1.73-3.61) vs. 2.60 (2.10-3.55) g; P = 0.93]. When using cut-point values of AVW established in another series of non-consecutive patients (n = 150, Cohort B) with NF and concordant Doppler-echocardiographic findings, we found that the percentage of patients with evidence of severe stenosis in Cohort A was 70% in patients with PLF-LG and 86% in patients with NF-HG. CONCLUSION: The aortic valve weight data reported in this study provide evidence that a large proportion of patients with PLF and low-gradient have a severe stenosis and that the gradient may substantially underestimate stenosis severity in these patients. A multi-parametric approach including all Doppler-echocardiographic parameters of valve function as well as other complementary diagnostic tests may help correctly identify these patients.

Paradoxical low flow aortic valve stenosis: incidence, evaluation, and clinical significance.

Paradoxical low-flow (PLF) aortic stenosis is defined by a stroke volume index <35 ml/m(2) despite the presence of preserved LV ejection fraction (≥ 50 %). This entity is typically characterized by pronounced LV concentric remodeling with small LV cavity, impaired LV filling, increased arterial load, and reduced LV longitudinal shortening. Patients with PLF also have a worse prognosis compared to patients with normal flow. Because of the low flow state, these patients often have a low gradient despite the presence of severe stenosis, thus leading to discordant AS grading (i.e., aortic valve area < 1.0 cm(2) but mean gradient < 40 mmHg) and thus uncertainty about the indication of aortic valve replacement. Stress echocardiography and aortic valve calcium score by computed tomography may be helpful to differentiate true from pseudo severe stenosis and thereby guide therapeutic management in these patients. Aortic valve replacement improves outcomes in patients with PLF low gradient AS having evidence of severe stenosis. Transcatheter aortic valve replacement may provide an interesting alternative to surgery in these patients.

Impact of hypertension and renin-angiotensin system inhibitors in aortic stenosis.

BACKGROUND: Experimental studies revealed that renin-angiotensin system (RAS) could play a crucial role in the pathophysiology of aortic stenosis (AS). The objectives of this study were to examine (i) the impact of hypertension on AS progression and clinical events and (ii) the effect of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin-receptor blockers (ARBs). MATERIALS AND METHODS: In this observational study, we retrospectively analysed clinical and Doppler echocardiographic data prospectively collected in 338 patients with AS. Patients were separated into four groups: patients without hypertension and not treated by RAS medication (Ctrl group), patients with hypertension but not treated by RAS medication (HTN group), patients treated with ACEIs, and patients treated with ARBs. AS progression rate was assessed by the annualized increase in peak aortic jet velocity. RESULTS: Compared with Ctrl group, patients in HTN group had faster stenosis progression (P = 0·01). Patients on ARBs had slower AS progression compared with Ctrl (trend P = 0·10) and HTN (P = 0·002) groups, whereas patients on ACEIs had similar progression rate compared with Ctrl group (P = NS) but lower compared with HTN group (P = 0·02). On multivariable analysis, compared with Ctrl group, HTN group was associated with faster AS progression rate (P = 0·002), whereas ARBs with slower progression (P = 0·0008). During a mean follow-up of 6·2 ± 2·4 years, HTN (hazard ratio [HR] = 2·45; P = 0·006) and ACEI (HR = 2·30; P = 0·01) groups were associated with a significant increase in all-cause mortality compared with Ctrl group, whereas ARB group (HR: 0·89; P = 0·80) not. In multivariable analysis, HTN and ACEI groups remained associated with increased mortality. CONCLUSIONS: Hypertension is associated with significantly faster stenosis progression and higher incidence of clinical events in patients with AS. ARBs but not ACEs were found to abolish the increased risk of mortality associated with hypertension.

Low-flow, low-gradient severe aortic stenosis in patients with normal ejection fraction.

PURPOSE OF REVIEW: The occurrence of low-flow low-gradient severe aortic stenosis in patients with normal left ventricle (LV) ejection fraction has only been recently described. The purpose of this review is to highlight the diagnostic and management specificities of this entity. RECENT FINDINGS: In the American College of Cardiology/American Heart Association guidelines, the criteria for severe aortic stenosis are an effective orifice area less than1.0 cm or less than 0.6 cm/m, a transvalvular mean gradient greater than 40 mmHg and a peak aortic jet velocity greater than 4.0 m/s. The guidelines also acknowledge that lower gradients may be observed in patients with depressed ejection fraction, with the implication that such an occurrence is not expected in patients with normal ejection fraction. However, recent studies confirm that a bona fide low-flow, low-gradient (LFLG) state may nonetheless be observed in 10-25% of patients with severe aortic stenosis and normal left ventricular ejection fraction (LVEF). This entity bears analogy with normal LVEF heart failure and is due to a restrictive physiology in relation with more pronounced LV concentric remodeling, a smaller LV cavity size and reductions in LV compliance and filling. SUMMARY: The clinical relevance of LFLG severe aortic stenosis is now recognized in the most recent European (European Society of Cardiology/European Association for Cardio-Thoracic Surgery) guidelines, which also emphasize that it should be confirmed as being due to low-flow conditions. In particular, patients with bona fide paradoxical LFLG aortic stenosis should be distinguished from patients with normal flow and low gradient because of inconsistent cutoff criteria because, among patients with severe aortic stenosis, the former have the worst prognosis, whereas the latter have the best.

Impact of aortic stenosis severity and its interaction with prosthesis-patient mismatch on operative mortality following aortic valve replacement.

BACKGROUND AND AIM OF THE STUDY: The optimal timing of aortic valve replacement (AVR) in patients with severe aortic stenosis (AS) is a source of debate. Moreover, it has been shown previously that prosthesis-patient mismatch (PPM) is an independent predictor of operative mortality after AVR. The study aim was to assess the effect of the preoperative severity of AS and its interaction with PPM with respect to operative mortality after AVR. METHODS: The data were analyzed from 2,104 consecutive patients who had undergone AVR for severe AS. The patients were allocated to tertiles according to their preoperative indexed aortic valve area (AVAi) as: < 0.35 cm2/m2, 0.35 to 0.43 cm2/m2, and > 0.43 cm2/m2. PPM was defined as a projected postoperative indexed effective orifice area (EOAi) of the implanted prosthesis < 0.85 cm2/m2. RESULTS: The operative mortality was 5.7% (n = 120). On multivariate analysis, an independent association was identified between the preoperative severity of AS and operative mortality (odds ratio [OR] = 2.00, p = 0.03 for AVAi < 0.35 cm2/m2; OR = 1.39, p = 0.32 for AVAi 0.35-0.43 cm2/m2). Notably, the impact of PPM was more important in patients with more severe AS (p = 0.046 for AVAi x EOAi interaction). CONCLUSION: The study results confirmed that very severe AS (AVAi < 0.35 cm2/m2) is independently associated with operative mortality after AVR. The results also emphasized the importance of avoiding PPM in these patients.

Effect of Lipid lowering with rosuvastatin on progression of aortic stenosis: results of the aortic stenosis progression observation: measuring effects of rosuvastatin (ASTRONOMER) trial.

BACKGROUND: Aortic stenosis (AS) is an active process with similarities to atherosclerosis. The objective of this study was to assess the effect of cholesterol lowering with rosuvastatin on the progression of AS. METHODS AND RESULTS: This was a randomized, double-blind, placebo-controlled trial in asymptomatic patients with mild to moderate AS and no clinical indications for cholesterol lowering. The patients were randomized to receive either placebo or rosuvastatin 40 mg daily. A total of 269 patients were randomized: 134 patients to rosuvastatin 40 mg daily and 135 patients to placebo. Annual echocardiograms were performed to assess AS progression, which was the primary outcome; the median follow-up was 3.5 years. The peak AS gradient increased in patients receiving rosuvastatin from a baseline of 40.8+/-11.1 to 57.8+/-22.7 mm Hg at the end of follow-up and in patients with placebo from 41.6+/-10.9 mm Hg at baseline to 54.8+/-19.8 mm Hg at the end of follow-up. The annualized increase in the peak AS gradient was 6.3+/-6.9 mm Hg in the rosuvastatin group and 6.1+/-8.2 mm Hg in the placebo group (P=0.83). Treatment with rosuvastatin was not associated with a reduction in AS progression in any of the predefined subgroups. CONCLUSIONS: Cholesterol lowering with rosuvastatin 40 mg did not reduce the progression of AS in patients with mild to moderate AS; thus, statins should not be used for the sole purpose of reducing the progression of AS. Clinical Trial Registration Information- URL: http://www.controlled-trials.com/. CLINICAL TRIAL REGISTRATION NUMBER: ISRCTN 32424163.

Effect of rosuvastatin on C-reactive protein and progression of aortic stenosis.

BACKGROUND: Elevated C-reactive protein (CRP) is a common finding in patients with aortic stenosis (AS) and may be associated with rapid AS progression and worse outcome. The purpose of the study was to examine the role of high-sensitivity CRP and its interaction with rosuvastatin on the progression of AS. METHODS: We measured CRP at baseline, 1 year, and end of follow-up in 260 patients with a median follow-up of 3.5 years. Analyses were performed based on baseline CRP tertiles and baseline CRP >3 and ≤3 mg/L. RESULTS: After adjustment for baseline characteristics, higher CRP levels were associated with age, female gender, body mass index, and lower high-density lipoprotein cholesterol levels but not with AS severity. Treatment with rosuvastatin led to a persistent decrease in CRP at 1 year and end of follow-up. Progression of AS was detected in patients in all 3 CRP tertiles, and rosuvastatin treatment had no impact on progression in all 3 tertiles. Similar findings were observed using CRP >3 mg/L as the cutpoint. Multiple linear regression showed that baseline AS velocity (P < .001), but not CRP, was the only predictor of progression of AS; age (P = .05) and baseline AS velocity (P < .001), but not CRP and rosuvastatin treatment, were predictors of outcome events. CONCLUSION: C-reactive protein does not predict severity, progression, and prognosis in patients with mild to moderate AS. Treatment with rosuvastatin reduces CRP levels but has no effect on the progression and clinical events of AS.

Evaluating the effectiveness of rosuvastatin in preventing the progression of diastolic dysfunction in aortic stenosis: A substudy of the aortic stenosis progression observation measuring effects of rosuvastatin (ASTRONOMER) study.

BACKGROUND: Tissue Doppler imaging (TDI) is a noninvasive echocardiographic method for the diagnosis of diastolic dysfunction in patients with varying degrees of aortic stenosis (AS). Little is known however, on the utility of TDI in the serial assessment of diastolic abnormalities in AS. OBJECTIVE: The aim of the current proposal was to examine whether treatment with rosuvastatin was successful in improving diastolic abnormalities in patients enrolled in the Aortic Stenosis Progression Observation Measuring Effects of Rosuvastatin (ASTRONOMER) study. METHODS: Conventional Doppler indices including peak early (E) and late (A) transmitral velocities, and E/A ratio were measured from spectral Doppler. Tissue Doppler measurements including early (E') and late (A') velocities of the lateral annulus were determined, and E/E' was calculated. RESULTS: The study population included 168 patients (56 ± 13 years), whose AS severity was categorized based on peak velocity at baseline (Group I: 2.5-3.0 m/s; Group II: 3.1-3.5 m/s; Group III: 3.6-4.0 m/s). Baseline and follow-up hemodynamics, LV dimensions and diastolic functional parameters were evaluated in all three groups. There was increased diastolic dysfunction from baseline to follow-up in each of the placebo and rosuvastatin groups. In patients with increasing severity of AS in Groups I and II, the lateral E' was lower and the E/E' (as an estimate of increased left ventricular end-diastolic pressure) was higher at baseline (p < 0.05). However, treatment with rosuvastatin did not affect the progression of diastolic dysfunction from baseline to 3.5 year follow-up between patients in any of the three predefined groups. CONCLUSION: In patients with mild to moderate asymptomatic AS, rosuvastatin did not attenuate the progression of diastolic dysfunction.

Prosthesis-patient mismatch: an update.

Prosthesis-patient mismatch (PPM) is present when the effective orifice area of the inserted prosthetic valve is too small in relation to body size. Its main hemodynamic consequence is to generate higher than expected gradients through normally functioning prosthetic valves. The purpose of this review is to present an update on the present state of knowledge with regard to diagnosis, prognosis, and prevention of PPM. PPM is a frequent occurrence (20% to 70% of aortic valve replacements) that has been shown to be associated with worse hemodynamics, less regression of left ventricular hypertrophy, more cardiac events, and lower survival. Moreover, as opposed to most other risk factors, PPM can largely be prevented by using a prospective strategy at the time of operation.

Paradoxical low flow and/or low gradient severe aortic stenosis despite preserved left ventricular ejection fraction: implications for diagnosis and treatment.

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.

Usefulness of exercise-stress echocardiography for risk stratification of true asymptomatic patients with aortic valve stenosis.

Aims Abnormal exercise test defined as the occurrence of exercise limiting symptoms, fall in blood pressure below baseline, or complex ventricular arrhythmias is useful to predict clinical events in asymptomatic patients with aortic stenosis (AS). The purpose of this study was to determine whether exercise-stress echocardiography (ESE) adds any incremental prognostic value to resting echocardiography in patients with AS having a normal exercise response. Methods and results One hundred and eighty-six asymptomatic patients with at least moderate AS and preserved LV ejection fraction (>/=50%) were assessed by Doppler-echocardiography at rest and during a maximum ramp semi-supine bicycle exercise test. Fifty-one (27%) patients had an abnormal exercise test and were excluded from the present analysis. Among the 135 patients with normal exercise test, 67 had an event (aortic valve replacement motivated by symptoms or cardiovascular death) at a mean follow-up of 20 +/- 14 months. The variables independently associated with events were: age >/=65 years [hazard ratio (HR) = 1.96; 95% confidence interval (CI): 1.15-3.47; P = 0.01], diabetes, (HR = 3.20; 95% CI: 1.33-6.87; P = 0.01), LV hypertrophy (HR = 1.96; 95% CI: 1.17-3.27; P = 0.01), resting mean gradient >35 mmHg (HR = 3.60; 95% CI: 2.11-6.37; P < 0.0001), and exercise-induced increase in mean gradient >20 mmHg (HR = 3.83; 95% CI: 2.16-6.67; P < 0.0001). Conclusion The exercise-induced increase in transvalvular gradient may be helpful to improve risk stratification in asymptomatic AS patients with normal exercise response. These results thus suggest that ESE may provide additional prognostic information over that obtained from standard exercise testing and resting echocardiography.

Mitral repair versus replacement for ischemic mitral regurgitation: comparison of short-term and long-term survival.

BACKGROUND: When compared to mitral valve replacement (MVR), mitral valve repair (MVRp) is associated with better survival in patients with organic mitral regurgitation (MR). However, there is an important controversy about the type of surgical treatment that should be used in patients with ischemic MR. The objective of this study was to compare the postoperative outcome of MVRp versus MVR in patients with ischemic MR. METHODS AND RESULTS: Preoperative and operative data of 370 patients with ischemic MR who underwent mitral valve surgery were prospectively collected and retrospectively analyzed. MVRp was performed in 50% of patients (n=186) and MVR in 50% (n=184). Although operative mortality was significantly lower after MVRp compared to MVR (9.7% versus 17.4%; P=0.03), overall 6-year survival was not statistically different between procedures (73+/-4% versus 67+/-4%; P=0.17). After adjusting for other risk factors and propensity score, the type of procedure (MVRp versus MVR) did not come out as an independent predictor of either operative (OR, 1.5; 95% CI, 0.7-2.9; P=0.34) or overall mortality (HR, 1.2; 95% CI, 0.7-1.9; P=0.52). CONCLUSIONS: As opposed to what has been reported in patients with organic MR, the results of this study suggest that MVRp is not superior to MVR with regard to operative and overall mortality in patients with ischemic MR. These findings provide support for the realization of a randomized trial comparing these 2 treatment modalities.

Association of Bicuspid aortic valve morphology and aortic root dimensions: a substudy of the aortic stenosis progression observation measuring effects of rosuvastatin (ASTRONOMER) study.

BACKGROUND: Bicuspid aortic valve (BAV) is the leading cause of aortic stenosis in patients younger than the age of 50. A classification scheme of BAVs is based upon leaflet orientation: Type I (fusion of right and left coronary cusps) and Type II (fusion of right and noncoronary cusps). The correlation between BAV leaflet orientation and aortic root pathology however remains ill defined. OBJECTIVE: The objective was to describe a potential relationship between BAV leaflet morphology and aortic root measurements in the ASTRONOMER study, a multicenter study to assess the effect of rosuvastatin on the progression of AS. METHODS: BAV morphology was classified as Type I or Type II orientation based on the parasternal short-axis view. Echo measurements including left ventricular and aortic root dimensions were obtained. RESULTS: The study population included 89 patients (56 +/- 11 years; 44 males). There were 63 patients with Type I and 26 patients with Type II BAV. Baseline demographics, hemodynamics, and left heart dimensions were similar between both groups. Patients with Type I BAV had larger aortic annulus and ascending root dimensions compared to those patients with Type II BAV (P < 0.05). CONCLUSION: In patients with mild to moderate aortic stenosis due to a BAV, the presence of Type I valve orientation was associated with significantly greater aortic root parameters compared to Type II valve orientation.

Usefulness and limitation of dobutamine stress echocardiography to predict acute response to cardiac resynchronization therapy.

BACKGROUND: It has been hypothesized that a long-term response to cardiac resynchronization therapy (CRT) could correlate with myocardial viability in patients with left ventricular (LV) dysfunction. Contractile reserve and viability in the region of the pacing lead have not been investigated in regard to acute response after CRT. METHODS: Fifty-one consecutive patients with advanced heart failure, LV ejection fraction 120 ms, and intraventricular asynchronism >or= 50 ms were prospectively included. The week before CRT implantation, the presence of viability was evaluated using dobutamine stress echocardiography. Acute responders were defined as a >or=15% increase in LV stroke volume. RESULTS: The average of viable segments was 5.8 +/- 1.9 in responders and 3.9 +/- 3 in nonresponders (P = 0.03). Viability in the region of the pacing lead had an excellent sensitivity (96%), but a low specificity (56%) to predict acute response to CRT. Mitral regurgitation (MR) was reduced in 21 patients (84%) with acute response. The presence of MR was a poor predictor of response (sensibility 93% and specificity 17%). However, combining the presence of MR and viability in the region of the pacing lead yields a sensibility (89%) and a specificity (70%) to predict acute response to CRT. CONCLUSION: Myocardial viability is an important factor influencing acute hemodynamic response to CRT. In acute responders, significant MR reduction is frequent. The combined presence of MR and viability in the region of the pacing lead predicts acute response to CRT with the best accuracy.

Low-flow, low-gradient, normal ejection fraction aortic stenosis.

A substantial proportion of patients with severe aortic stenosis may paradoxically have low transvalvular flow and a low gradient, despite the presence of normal left ventricular (LV) ejection fraction. These patients are characterized by pronounced LV concentric remodeling with small LV cavity size, impaired LV filling, altered myocardial function, and worse prognosis. This frequent clinical entity is often misdiagnosed, which may lead to an underestimation of aortic stenosis severity and thereby to underutilization or inappropriate delay of surgery. It is important to recognize this entity so we do not deny surgery to a symptomatic patient with small aortic valve area and low gradient. Thus, when there is a discordance between the valve area (in the severe range) and the gradient (in the moderate range) in patients with preserved LV ejection fraction, a more comprehensive Doppler echocardiographic evaluation and potentially other diagnostic tests may be required to confirm disease severity and guide therapeutic management.

ApoCIII-Lp(a) complexes in conjunction with Lp(a)-OxPL predict rapid progression of aortic stenosis.

OBJECTIVE: This study assessed whether apolipoprotein CIII-lipoprotein(a) complexes (ApoCIII-Lp(a)) associate with progression of calcific aortic valve stenosis (AS). METHODS: Immunostaining for ApoC-III was performed in explanted aortic valve leaflets in 68 patients with leaflet pathological grades of 1-4. Assays measuring circulating levels of ApoCIII-Lp(a) complexes were measured in 218 patients with mild-moderate AS from the AS Progression Observation: Measuring Effects of Rosuvastatin (ASTRONOMER) trial. The progression rate of AS, measured as annualised changes in peak aortic jet velocity (Vpeak), and combined rates of aortic valve replacement (AVR) and cardiac death were determined. For further confirmation of the assay data, a proteomic analysis of purified Lp(a) was performed to confirm the presence of apoC-III on Lp(a). RESULTS: Immunohistochemically detected ApoC-III was prominent in all grades of leaflet lesion severity. Significant interactions were present between ApoCIII-Lp(a) and Lp(a), oxidised phospholipids on apolipoprotein B-100 (OxPL-apoB) or on apolipoprotein (a) (OxPL-apo(a)) with annualised Vpeak (all p<0.05). After multivariable adjustment, patients in the top tertile of both apoCIII-Lp(a) and Lp(a) had significantly higher annualised Vpeak (p<0.001) and risk of AVR/cardiac death (p=0.03). Similar results were noted with OxPL-apoB and OxPL-apo(a). There was no association between autotaxin (ATX) on ApoB and ATX on Lp(a) with faster progression of AS. Proteomic analysis of purified Lp(a) showed that apoC-III was prominently present on Lp(a). CONCLUSION: ApoC-III is present on Lp(a) and in aortic valve leaflets. Elevated levels of ApoCIII-Lp(a) complexes in conjunction with Lp(a), OxPL-apoB or OxPL-apo(a) identify patients with pre-existing mild-moderate AS who display rapid progression of AS and higher rates of AVR/cardiac death. TRIAL REGISTRATION: NCT00800800.

Predictors of outcomes in low-flow, low-gradient aortic stenosis: results of the multicenter TOPAS Study.

BACKGROUND: Patients with low-flow, low-gradient aortic stenosis have a poor prognosis with conservative therapy but a high operative mortality if treated surgically. Recently, we proposed a new index of aortic stenosis severity derived from dobutamine stress echocardiography, the projected aortic valve area at a normal transvalvular flow rate, as superior to other conventional indices to differentiate true-severe from pseudosevere aortic stenosis. The objective of this study was to identify the determinants of survival, functional status, and change in left ventricular ejection fraction during follow-up of patients with low-flow, low-gradient aortic stenosis. METHODS AND RESULTS: One hundred one patients with low-flow, low-gradient aortic stenosis (aortic valve area