Ian G. Burwash

Prospective Study of Asymptomatic Valvular Aortic Stenosis Clinical, Echocardiographic, and Exercise Predictors of Outcome

BACKGROUND Only limited data on the rate of hemodynamic progression and predictors of outcome in asymptomatic patients with valvular aortic stenosis (AS) are available. METHODS AND RESULTS In 123 adults (mean age, 63 +/- 16 years) with asymptomatic AS, annual clinical, echocardiographic, and exercise data were obtained prospectively (mean follow-up of 2.5 +/- 1.4 years). Aortic jet velocity increased by 0.32 +/- 0.34 m/s per year and mean gradient by 7 +/- 7 mm Hg per year; valve area decreased by 0.12 +/- 0.19 cm2 per year. Kaplan-Meier event-free survival, with end points defined as death (n = 8) or aortic valve surgery (n = 48), was 93 +/- 5% at 1 year, 62 +/- 8% at 3 years, and 26 +/- 10% at 5 years. Univariate predictors of outcome included baseline jet velocity, mean gradient, valve area, and the rate of increase in jet velocity (all P < or = .001) but not age, sex, or cause of AS. Those with an end point had a smaller exercise increase in valve area, blood pressure, and cardiac output and a greater exercise decrease in stroke volume. Multivariate predictors of outcome were jet velocity at baseline (P < .0001), the rate of change in jet velocity (P < .0001), and functional status score (P = .002). The likelihood of remaining alive without valve replacement at 2 years was only 21 +/- 18% for a jet velocity at entry > 4.0 m/s, compared with 66 +/- 13% for a velocity of 3.0 to 4.0 m/s and 84 +/- 16% for a jet velocity < 3.0 m/s (P < .0001). CONCLUSIONS In adults with asymptomatic AS, the rate of hemodynamic progression and clinical outcome are predicted by jet velocity, the rate of change in jet velocity, and functional status.

Comparison Between Transcatheter and Surgical Prosthetic Valve Implantation in Patients With Severe Aortic Stenosis and Reduced Left Ventricular Ejection Fraction

Background— Patients with severe aortic stenosis and reduced left ventricular ejection fraction (LVEF) have a poor prognosis with conservative therapy but a high operative mortality when treated surgically. Recently, transcatheter aortic valve implantation (TAVI) has emerged as an alternative to surgical aortic valve replacement (SAVR) for patients considered at high or prohibitive operative risk. The objective of this study was to compare TAVI and SAVR with respect to postoperative recovery of LVEF in patients with severe aortic stenosis and reduced LV systolic function. Methods and Results— Echocardiographic data were prospectively collected before and after the procedure in 200 patients undergoing SAVR and 83 patients undergoing TAVI for severe aortic stenosis (aortic valve area ≤1 cm2) with reduced LV systolic function (LVEF ≤50%). TAVI patients were significantly older (81±8 versus 70±10 years; P<0.0001) and had more comorbidities compared with SAVR patients. Despite similar baseline LVEF (34±11% versus 34±10%), TAVI patients had better recovery of LVEF compared with SAVR patients (&Dgr;LVEF, 14±15% versus 7±11%; P=0.005). At the 1-year follow-up, 58% of TAVI patients had a normalization of LVEF (>50%) as opposed to 20% in the SAVR group. On multivariable analysis, female gender (P=0.004), lower LVEF at baseline (P=0.005), absence of atrial fibrillation (P=0.01), TAVI (P=0.007), and larger increase in aortic valve area after the procedure (P=0.01) were independently associated with better recovery of LVEF. Conclusion— In patients with severe aortic stenosis and depressed LV systolic function, TAVI is associated with better LVEF recovery compared with SAVR. TAVI may provide an interesting alternative to SAVR in patients with depressed LV systolic function considered at high surgical risk.

Effect of Cardiac Resynchronization on Myocardial Efficiency and Regional Oxidative Metabolism

Background—Recent studies have demonstrated increased left ventricular contractility with cardiac resynchronization therapy (CRT) using atriobiventricular stimulation. This study evaluated the effect of CRT on myocardial oxidative metabolism and efficiency. Methods and Results—Eight patients with New York Heart Association functional class III-IV congestive heart failure were studied during atrial pacing (control) and atriobiventricular stimulation at the same rate. The monoexponential clearance rate of [11C]acetate (kmono) was measured with positron emission tomography to assess myocardial oxidative metabolism in the left and right ventricles (LV and RV, respectively). Myocardial efficiency was measured using the work metabolic index (WMI). Stroke volume index improved by 10% (P =0.011) with CRT, although both global LV and RV kmono were unchanged compared with control. Septal kmono increased by 15% (P =0.04), and the septal/lateral wall kmono ratio increased by 22% (P =0.01). WMI increased by 13% (P =0.024) with CRT. Conclusions—CRT improves LV function without increasing global LV oxidative metabolism, resulting in improved myocardial efficiency. Oxidative metabolism of the interventricular septum increases relative to the lateral wall, which suggests successful resynchronization.

Dependence of Gorlin formula and continuity equation valve areas on transvalvular volume flow rate in valvular aortic stenosis.

BackgroundValve areas derived by the Gorlin formula have been observed to vary with transvalvular volume flow rate. Continuity equation valve areas calculated from Doppler- echo data have become a widely used alternate index of stenosis severity, but it is unclear whether continuity equation valve areas also vary with volume flow rate. This study was designed to investigate the effects of changing transvalvular volume flow rate on aortic valve areas calculated using both the Gorlin formula and the continuity equation in a model of chronic valvular aortic stenosis. Methods and ResultsUsing a canine model of chronic valvular aortic stenosis in which anatomy and hemodynamics are similar to those of degenerative aortic stenosis, each subject (n=8) underwent three studies at 2-week intervals. In each study, transvalvular volume flow rates were altered with saline or dobutamine infusion (mean, 10.3±5.1 flow rates per study). Simultaneous measurements were made of hemodynamics using micromanometer-tipped catheters, of ascending aortic instantaneous volume flow rate using a transit-time flowmeter, and of left ventricular outflow and aortic jet velocity curves using Doppler echocardiography. Valve areas were calculated from the invasive data by the Gorlin equation and from the Doppler-echo data by the continuity equation. In the 24 studies, mean transit-time transvalvular volume flow rate ranged from 80±33 to 153±49 mL/min (P < .0001). Comparing minimum to maximum mean volume flow rates, the Gorlin valve area changed from 0.54±0.22 cm2 to 0.68±0.21 cm2 (P < .0001), and the continuity equation valve area changed from 0.57±0.18 cm2 to 0.70±0.20 cm2 (P < .0001). A strong linear relation was observed between Gorlin valve area and mean transit-time volume flow rate for each study (median, r = .88), but the slope of this relation varied between studies. The Doppler-echo continuity equation valve area had a weaker linear relation with transit-time volume flow rate for each study (median, r = .51). ConclusionsIn this model of chronic valvular aortic stenosis, both Gorlin and continuity equation valve areas were flow-dependent indices of stenosis severity and demonstrated linear relations with transvalvular volume flow rate. The changes in calculated valve area that occur with changes in transvalvular volume flow should be considered when measures of valve area are used to assess the hemodynamic severity of valvular aortic stenosis.

Projected Valve Area at Normal Flow Rate Improves the Assessment of Stenosis Severity in Patients With Low-Flow, Low-Gradient Aortic Stenosis The Multicenter TOPAS (Truly or Pseudo-Severe Aortic Stenosis) Study

Background— We sought to investigate the use of a new parameter, the projected effective orifice area (EOAproj) at normal transvalvular flow rate (250 mL/s), to better differentiate between truly severe (TS) and pseudo-severe (PS) aortic stenosis (AS) during dobutamine stress echocardiography (DSE). Changes in various parameters of stenosis severity have been used to differentiate between TS and PS AS during DSE. However, the magnitude of these changes lacks standardization because they are dependent on the variable magnitude of the transvalvular flow change occurring during DSE. Methods and Results— The use of EOAproj to differentiate TS from PS AS was investigated in an in vitro model and in 23 patients with low-flow AS (indexed EOA <0.6 cm2/m2, left ventricular ejection fraction ≤40%) undergoing DSE and subsequent aortic valve replacement. For an individual valve, EOA was plotted against transvalvular flow (Q) at each dobutamine stage, and valve compliance (VC) was derived as the slope of the regression line fitted to the EOA versus Q plot; EOAproj was calculated as EOAproj=EOArest+VC×(250−Qrest), where EOArest and Qrest are the EOA and Q at rest. Classification between TS and PS was based on either response to flow increase (in vitro) or visual inspection at surgery (in vivo). EOAproj was the most accurate parameter in differentiating between TS and PS both in vitro and in vivo. In vivo, 15 of 23 patients (65%) had TS and 8 of 23 (35%) had PS. The percentage of correct classification was 83% for EOAproj and 91% for indexed EOAproj compared with percentages of 61% to 74% for the other echocardiographic parameters usually used for this purpose. Conclusions— EOAproj provides a standardized evaluation of AS severity with DSE and improves the diagnostic accuracy for distinguishing TS and PS AS in patients with low-flow, low-gradient AS.

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 ≤1.2 cm2, left ventricular ejection fraction ≤40%, and mean gradient ≤40 mm Hg) underwent dobutamine stress echocardiography and an assessment of functional capacity using the Duke Activity Status Index. A subset of 72 patients also underwent a 6-minute walk test. Overall survival was 70±5% at 1 year and 57±6% at 3 years. After adjusting for age, gender, and the type of treatment (aortic valve replacement versus no aortic valve replacement), significant predictors of mortality during follow-up were a Duke Activity Status Index ≤20 (P=0.0005) or 6-minute walk test distance ≤320 m (P<0.0001, in the subset of 72 patients), projected aortic valve area at a normal transvalvular flow rate ≤1.2 cm2 (P=0.03), and peak dobutamine stress echocardiography left ventricular ejection fraction ≤35% (P=0.03). More severe stenosis, defined as projected aortic valve area ≤1.2 cm2, was a predictor of mortality only in the no aortic valve replacement group. The Duke Activity Status Index, 6-minute walk test, and left ventricular ejection fraction improved significantly during follow-up in the aortic valve replacement group, but remained unchanged or decreased in the no aortic valve replacement group. Conclusion— In patients with low-flow, low-gradient aortic stenosis, the most significant risk factors for poor outcome were (1) impaired functional capacity as measured by Duke Activity Status Index or 6-minute walk test distance; (2) more severe valve stenosis as measured by projected aortic valve area at a normal transvalvular flow rate; and (3) reduced peak stress left ventricular ejection fraction, a composite measure accounting for both resting left ventricular function and contractile reserve.

B-type natriuretic peptide in low-flow, low-gradient aortic stenosis : Relationship to hemodynamics and clinical outcome: Results from the multicenter truly or pseudo-severe aortic stenosis (TOPAS) study

Background— The prognostic value of B-type natriuretic peptide (BNP) is unknown in low-flow, low-gradient aortic stenosis (AS). We sought to evaluate the relationship between AS and rest, stress hemodynamics, and clinical outcome. Methods and Results— BNP was measured in 69 patients with low-flow AS (indexed effective orifice area <0.6 cm2/m2, mean gradient ≤40 mm Hg, left ventricular ejection fraction ≤40%). All patients underwent dobutamine stress echocardiography and were classified as truly severe or pseudosevere AS by their projected effective orifice area at normal flow rate of 250 mL/s (effective orifice area ≤1.0 cm2 or >1.0 cm2). BNP was inversely related to ejection fraction at rest (Spearman correlation coefficient rs=−0.59, P<0.0001) and at peak stress (rs=−0.51, P<0.0001), effective orifice area at rest (rs=−0.50, P<0.0001) and at peak stress (rs=−0.46, P=0.0002), and mean transvalvular flow (rs=−0.31, P=0.01). BNP was directly related to valvular resistance (rs=0.42, P=0.0006) and wall motion score index (rs=0.36, P=0.004). BNP was higher in 29 patients with truly severe AS versus 40 with pseudosevere AS (median, 743 pg/mL [Q1, 471; Q3, 1356] versus 394 pg/mL [Q1, 191 to Q3, 906], P=0.012). BNP was a strong predictor of outcome. In the total cohort, cumulative 1-year survival of patients with BNP ≥550 pg/mL was only 47±9% versus 97±3% with BNP <550 (P<0.0001). In 29 patients who underwent valve replacement, postoperative 1-year survival was also markedly lower in patients with BNP ≥550 pg/mL (53±13% versus 92±7%). Conclusions— BNP is significantly higher in truly severe than pseudosevere low-gradient AS and predicts survival of the whole cohort and in patients undergoing valve replacement.

Physiologic changes with maximal exercise in asymptomatic valvular aortic stenosis assessed by Doppler echocardiography.

OBJECTIVES We hypothesized that the physiologic response to exercise in valvular aortic stenosis could be measured by Doppler echocardiography. BACKGROUND Data on exercise hemodynamics in patients with aortic stenosis are limited, yet Doppler echocardiography provides accurate, noninvasive measures of stenosis severity. METHODS In 28 asymptomatic subjects with aortic stenosis maximal treadmill exercise testing was performed with Doppler recordings of left ventricular outflow tract and aortic jet velocities immediately before and after exercise. Maximal and mean volume flow rate (Qmax and Qmean), stroke volume, cardiac output, maximal and mean aortic jet velocity (Vmax, Vmean), mean pressure gradient (delta P) and continuity equation aortic valve area were calculated at rest and after exercise. The actual change from rest to exercise in Qmax and Vmax was compared with the predicted relation between these variables for a given orifice area. Subjects were classified into two groups: Group I (rest-exercise Vmax/Qmax slope > 0, n = 19) and Group II (slope < or = 0, n = 9). RESULTS Mean exercise duration was 6.7 +/- 4.3 min. With exercise, Vmax increased from 3.99 +/- 0.93 to 4.61 +/- 1.12 m/s (p < 0.0001) and mean delta P increased from 39 +/- 20 to 52 +/- 26 mm Hg (p < 0.0001). Qmax rose with exercise (422 +/- 117 to 523 +/- 209 ml/s, p < 0.0001), but the systolic ejection period decreased (0.33 +/- 0.04 to 0.24 +/- 0.04, p < 0.0001), so that stroke volume decreased slightly (98 +/- 29 to 89 +/- 32 ml, p = 0.01). The increase in cardiac output with exercise (6.5 +/- 1.7 to 10.2 +/- 4.4 liters/min, p < 0.0001) was mediated by increased heart rate (71 +/- 17 to 147 +/- 28 beats/min, p < 0.0001). There was no significant change in the mean aortic valve area with exercise (1.17 +/- 0.45 to 1.28 +/- 0.65, p = 0.06). Compared with Group I patients, patients with a rest-exercise slope < or = 0 (Group II) tended to be older (69 +/- 12 vs. 58 +/- 19 years, p = 0.07) and had a trend toward a shorter exercise duration (5.3 +/- 2.9 vs. 7.3 +/- 4.9 min, p = 0.20). There was no difference between groups for heart rate at rest, blood pressure, stroke volume, cardiac output, Vmax, mean delta P or aortic valve area. With exercise, Group II subjects had a lower cardiac output (7.4 +/- 2.4 vs. 11.5 +/- 4.6 liters/min, p = 0.005) and a smaller percent increase in Vmax (3 +/- 9% vs. 22 +/- 14%, p < 0.0001). CONCLUSIONS Doppler echocardiography allows assessment of physiologic changes with exercise in adults with asymptomatic aortic stenosis. A majority of subjects show a rest-exercise response that closely parallels the predicted relation between Vmax and Qmax for a given orifice area. The potential utility of this approach for elucidating the relation between hemodynamic severity and clinical symptoms deserves further study.

Flow dependence of measures of aortic stenosis severity during exercise

OBJECTIVES This study was designed to investigate the effect of altering transvalvular volume flow rate on indexes of aortic stenosis severity (valve area, valve resistance, percent left ventricular stroke work loss) derived by using Doppler echocardiography. BACKGROUND Assessment of hemodynamic severity in aortic stenosis has been limited by the absence of an index that is independent of transvalvular flow rate. The traditional measurement of valve area by the Gorlin equation has been shown to vary with alterations in transvalvular flow. Recently, valve resistance and percent stroke work loss have been proposed as indexes that are relatively independent of flow. Although typically derived with invasive measurements, valve resistance and percent stroke work loss (in addition to continuity equation valve area) can be determined noninvasively with Doppler echocardiography. METHODS We performed 110 symptom-limited exercise studies in 66 asymptomatic patients with valvular aortic stenosis. Continuity equation valve area, valve resistance (the ratio between mean transvalvular pressure gradient and mean flow rate) and the steady component of percent stroke work loss (the ratio between mean transvalvular pressure gradient and left ventricular systolic pressure) were assessed by Doppler echocardiography at rest and immediately after exercise. RESULTS Mean transvalvular volume flow rate increased 24% (from [mean +/- SD] 319 +/- 80 to 400 +/- 140 ml/s, p < 0.0001); mean pressure gradient increased 36% (from 30 +/- 14 to 41 +/- 18 mm Hg, p < 0.0001); continuity equation aortic valve area increased 14% (from 1.38 +/- 0.50 to 1.58 +/- 0.69 cm2, p < 0.0001); valve resistance increased 13% (from 137 +/- 81 to 155 +/- 97 dynes.s.cm-5, p < 0.0001); and percent stroke work loss increased 17% (from 17.4 +/- 6.9% to 20.3 +/- 8.5%, p < 0.0001). The effects of flow on valve area, valve resistance and percent stroke work loss were independent of the presence of an aortic valve area < or = or > 1.0 cm2 or reduced transvalvular flow rate (rest cardiac output < 4.5 liters/min). CONCLUSIONS In patients with asymptomatic aortic stenosis, Doppler echocardiographic measures of valve area, valve resistance and percent stroke work loss are flow dependent. Flow dependence is observed with valve area < or = or > 1.0 cm2 and in the presence of both normal and low transvalvular flow states. The potential effects of transvalvular flow should be considered when interpreting Doppler measures of aortic stenosis severity.

Long-term outcomes after valve replacement for low-gradient aortic stenosis: impact of prosthesis-patient mismatch.

Background— The long-term outcomes of patients with low-gradient aortic stenosis (LGAS) after aortic valve replacement (AVR) are poorly defined. The purpose of this study was to define the long-term outcomes of LGAS patients after AVR and to evaluate the potential impact of prosthesis–patient mismatch (PPM) in these patients. Methods and Results— A cohort of 664 patients undergoing AVR for aortic stenosis after 1990 were followed-up prospectively with annual clinical assessment and echocardiography (total follow-up 3447 patient-years; mean follow-up 5.2±3.3 years). LGAS was defined as an aortic valve area <1.2 cm2, a mean transvalvular pressure gradient <40 mm Hg, and a left ventricular (LV) ejection fraction <50%, and was present in 79 patients. Rates and correlates of survival, freedom from congestive heart failure (CHF), and LV mass regression after AVR were determined using multivariate regression methods. Ten-year survival and freedom from CHF after AVR were 72.7±7.5% and 68.2±9.5%, respectively, for patients with LGAS, compared with 89.6±1.8% and 84.1±4.2% for patients without LGAS (hazard ratio [HR] for death and postoperative CHF, 3.1±1.1 and 2.7±0.9, respectively; P<0.01). In LGAS patients, PPM, defined as an indexed effective orifice area ≤0.85 cm2/m2, was independently associated with increased rates of CHF (HR, 3.6±2.2; P=0.039), impaired LV mass regression (P=0.037), and a trend toward increased late mortality (HR, 3.0±1.9; P=0.084). Conclusions— Patients with LGAS have worse long-term outcomes after AVR compared with patients without LGAS. PPM adversely affects the long-term outcomes of LGAS patients and should be avoided in this population.