Severe Aortic Stenosis With Low Transvalvular Gradient and Severe Left Ventricular Dysfunction

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1 Severe Aortic Stenosis With Low Transvalvular Gradient and Severe Left Ventricular Dysfunction Result of Aortic Valve Replacement in 52 Patients Heidi M. Connolly, MD; Jae K. Oh, MD; Hartzell V. Schaff, MD; Veronique L. Roger, MD; Sara L. Osborn, CCRA; David O. Hodge, MS; A. Jamil Tajik, MD Background The outcome of aortic valve replacement in patients with severe aortic stenosis, low transvalvular gradient, and severe left ventricular dysfunction is not well known. Methods and Results Between 1985 and 1995, 52 patients with left ventricular ejection fraction (EF) 35% and aortic stenosis with transvalvular mean gradient 30 mm Hg underwent aortic valve replacement. The mean ( SD) preoperative characteristics included EF, 26 8%; aortic valve mean gradient, 23 4 mm Hg; aortic valve area, cm 2 ; and cardiac output, L/min. Simultaneous coronary artery bypass graft surgery was performed in 32 patients (62%). Perioperative (30-day) mortality was 21% (11 of 52 patients). Ten additional patients died during follow-up. Advanced age (P 0.048) and small aortic prosthesis size (P 0.03) were significant predictors of hospital mortality by univariate analysis. By multivariate analysis, the only predictor of surgical mortality was smaller prosthesis size. The only predictor of postoperative survival was improvement in postoperative functional class (P 0.04). Postoperative functional improvement occurred in most patients. Postoperative EF was assessed in 93% of survivors; 74% demonstrated improvement. Positive change in EF was related to smaller preoperative aortic valve area and female sex. Conclusions Despite severe left ventricular dysfunction, low transvalvular mean gradient, and increased operative mortality, aortic valve replacement was associated with improved functional status. Postoperative survival was related to younger patient age and larger aortic prosthesis size, and medium-term survival was related to improved postoperative functional class. (Circulation. 2000;101: ) Key Words: prognosis stenosis valves ventricles Severe aortic stenosis carries a dismal prognosis when associated with congestive heart failure, with an expected survival of 2 years when treated medically. 1 Aortic valve replacement is the only effective treatment, but the operative risk 2 increases with the development of left ventricular (LV) systolic dysfunction. 3 7 See p 1892 The results of aortic valve replacement are uncertain among patients with severe aortic stenosis, reduced LV ejection fraction (LVEF), and low transvalvular mean gradient. Although these patients represent 5% of patients with aortic stenosis, they also represent the most controversial subset. Increased perioperative risk and reduced late outcome compared with controls have been reported in patients with reduced LVEF. 7 LV dysfunction may be secondary to longstanding severe aortic stenosis with superimposed myocardial fibrosis, extensive coronary artery disease, or prior myocardial infarction, and in this situation, the LV dysfunction is not likely to improve after aortic valve replacement. Some have therefore suggested that aortic valve replacement should not be considered in this subgroup of patients. 8 Few data are available on the clinical outcome of patients with aortic stenosis, decreased LVEF, and low transvalvular mean gradient who undergo aortic valve replacement. Therefore, we tested the hypothesis that aortic valve replacement in patients with aortic stenosis, LVEF 35%, and transvalvular mean gradient 30 mm Hg can be performed at an acceptable operative and medium-term risk and that clinical and EF improvement occur in the majority of surgical survivors. Methods Study Population From the Mayo Clinic surgical database, we identified all patients who had aortic valve replacement for native aortic stenosis in the presence of severe LV systolic dysfunction (EF 35%) and associated low transvalvular mean gradient (mean gradient 30 mm Hg) between 1985 and We previously reported the outcome of aortic valve replacement in patients with aortic stenosis and reduced LVEF. 7 Twenty-nine of the patients included in the present series were included in our previous report. Patients were excluded if they Received September 9, 1999; revision received November 19, 1999; accepted December 2, From the Division of Cardiovascular Diseases and Internal Medicine (H.M.C., J.K.O., V.L.R., S.L.O., A.J.T.), the Section of Cardiovascular Surgery (H.V.S.), and the Section of Biostatistics (D.O.H.), Mayo Clinic and Mayo Foundation, Rochester, Minn. Reprint requests to Heidi M. Connolly, MD, Mayo Clinic, 200 First St SW, Rochester, MN American Heart Association, Inc. Circulation is available at

2 Connolly et al Aortic Valve Replacement 1941 TABLE 1. Clinical and Hemodynamic Data Gathered From the Medical Records of 52 Patients Characteristic Finding Age, y, mean SD (range) (23 89) Sex, M F Body surface area, m 2, mean SD (range) ( ) Preoperative symptoms, n (%) Dyspnea 49 (94) Angina 26 (50) Syncope 4 (8) Cardiogenic shock 1 (2) NYHA class, n I 2 II 5 III 27 IV 17 ECG, n (%) LV hypertrophy 20 (38) Left bundle-branch block 10 (19) Rhythm Sinus 40 (77) Atrial fibrillation 7 (13) Paced 5 (10) Prior MI (history), n (%) 21 (40) Prior MI by ECG, n (%) Inferior 7 (13) Anterior 3 (5) Non Q-wave 8 (15) History of MI, no coronary artery disease by 3 (6) angiography Prior procedures, n (%) Percutaneous aortic valvuloplasty 1 (2) Coronary artery bypass graft surgery 6 (12) PTCA 1 (2) LVEF, %, mean SD (range) 26 8 (10 35) LVEF assessment, n Echocardiography 49 Calculated 42 Estimated 7 LV angiography 3 LV size (EDD), mm, mean SD (range) (22 83) (n 28) LV septal diastolic wall thickness, mm, 12 3 (8 18) mean SD (range) (n 28) LV posterior diastolic wall thickness, mm, 10 3 (6 19) mean SD (range) (n 28) Mean transvalvular gradient, mm Hg (range) 23 4 (13 29) Aortic valve area, cm 2, mean SD (range) ( ) (42 echo, 10 cath) Cardiac output, L/min, mean SD (range) ( ) (n 50) Cardiac index, L min 1 m 2, mean SD ( ) (range) (n 43) TABLE 1. Continued Characteristic Finding Peak aortic velocity, m/s, mean SD (range) ( ) Coronary angiography, n (%) 50 (96) Coronary artery disease, n (%) 36 (69) M F ratio Creatinine level, mg/dl, mean SD (range) ( ) Comorbidities, No. of patients (%) Systemic hypertension 28 (54) Diabetes mellitus 15 (29) Peripheral vascular disease 15 (29) Carotid disease 8 (15) Chronic obstructive lung disease 7 (13.5) Liver disease 4 (8) MI indicates myocardial infarction; EDD, end-diastolic diameter. had concomitant valvular operations other than aortic valve replacement, previous aortic valve replacement, or more than moderate aortic valve regurgitation or were 18 years old. Preoperative clinical, echocardiographic, cardiac catheterization, hemodynamic, coronary artery (Table 1), and operative (Table 2) data were reviewed in 52 consecutive patients who fulfilled entry criteria. Echocardiography Comprehensive 2D and Doppler echocardiographic assessment 30 was performed at the Mayo Clinic in 50 patients (96%) 30 days before aortic valve replacement. The EF was calculated by 2D echocardiography with a modification of the method of Quinones et al 10,11 in 17 patients, by the volumetric method 12 in 25 patients, and by visual estimate 13,14 in 10 patients. Hemodynamic assessment of aortic stenosis was performed by 2D/Doppler methodology, and AVA was calculated by the continuity equation. 15 Cardiac Catheterization Forty patients (77%) had preoperative hemodynamic assessment by cardiac catheterization. With fluid-filled catheters, LV and systemic arterial pressures were recorded simultaneously. Cardiac output and index were measured, and AVA was calculated from the Gorlin equation. 16 Coronary angiography was performed in 50 patients (96%) (mean age SD, 72 9 years). Coronary artery stenosis was defined as a luminal diameter narrowing of 70% in 1 of the major epicardial coronary arteries or 50% luminal diameter narrowing of the left main coronary artery. When 1 method was used to define preoperative EF, mean pressure gradient, or AVA, the result of the echocardiographic Doppler method was used when it was performed up to 30 days before aortic valve replacement. The mean AVA (Table 1) was obtained by echocardiographic Doppler technique in 42 patients and by cardiac catheterization in 10 patients. 17 Surgical Procedures The surgical data are outlined in Table 2. Statistical Analysis The data are reported as mean SD. The relationship, univariate and multivariate, of potential risk factors with operative mortality (ie, death within 30 days after operation) was assessed by logistic regression analysis. Overall survival was estimated by the Kaplan- Meier method, and the predictors were analyzed by the Cox proportional hazards model. The relationship of preoperative variables to postoperative EF was assessed by simple and multiple linear regression.

3 1942 Circulation April 25, 2000 TABLE 2. Surgical Data Gathered From the Records of 52 Patients Variable Finding Urgency of operation, n (%) Elective 42 (81) Urgent 7 (13) Emergent 3 (6) Simultaneous procedures, n (%) 32 (62) Coronary artery bypass graft, n (%) 32 (62) M F ratio 9 23 Vein grafts, 1, 2, 3 12, 14, 4 Internal mammary graft 10 Aortic root enlargement, n (%) 9 (17) Aortic prosthesis size, mm 23 2 Aortic valve replacement size, No. of patients Aortic prosthesis type, n (%) Bioprosthesis 36 (69) Carpentier-Edwards 27 Hancock 6 Ionescu-Shiley 2 Medtronic Intact 1 Mechanical 16 (31) St Jude 11 Medtronic-Hall 3 Starr-Edwards 2 Cardiopulmonary bypass time, min, mean SD (range) Cross-clamp time, min, mean SD (range) Results The preoperative clinical and hemodynamic data are outlined in Table 1. The surgical procedures and data are outlined in Table 2. Clinical Outcome (44 214) (32 159) Cardioplegia, No. of patients (%) Blood 29 (56) Blood retrograde 8 (15) Crystalloid 23 (44) Warm 7 (13) Cold 45 (87) Hospital Mortality The 30-day mortality was 21% (11 of 52 patients). Univariate analysis for operative mortality identified 2 significant preoperative risk factors: a smaller prosthesis size (P 0.03) and TABLE 3. Perioperative Mortality and Prosthesis Size, Patient Age, and Preoperative NYHA Class Patients, n Perioperative deaths, n AVR size Total Age group, y Total NYHA class I 2 2 II 5 1 III 27 4 IV 17 4 Total AVR indicates aortic valve replacement. advanced age at operation (P 0.048) (Table 3). The mean aortic prosthesis size was mm in survivors and mm in patients who died perioperatively. The mean age was years for survivors and 77 8 years for patients who died perioperatively. Multivariate analysis identified prosthesis size as the only predictor of hospital mortality. Body surface area was not significantly related to hospital mortality. Overall Survival Ten patients (Table 4) died during a median follow-up of 1.5 years (up to 3.9 years). Two patients were lost to follow-up. Two of the late deaths were from noncardiac causes. The survival of this patient group was 62% at 3 years (Figure 1). TABLE 4. Data on 10 Late Deaths Age at NYHA Class EF, % Surgery, y AVR Size Preop Postop Preop Postop III I III III IV II IV III II III III I III III II NA IV NA 25 NA II NA AVR indicates aortic valve replacement.

4 Connolly et al Aortic Valve Replacement 1943 Figure 2. Comparison of preoperative (preop) and postoperative (postop) NYHA functional class. Figure 1. A, Kaplan-Meier survival curve for patients with aortic stenosis, decreased LV function, and low transvalvular mean gradient (MG) compared with expected survival. B, Kaplan- Meier survival curve for patients with aortic stenosis, decreased LV function, and low MG ( 30 mm Hg) compared with patients with aortic stenosis, decreased LV function, and MG 30 mm Hg. The survival in the study group was significantly lower (P 0.04) than survival among the 128 patients who underwent aortic valve replacement for aortic stenosis, with mean gradient 30 mm Hg previously reported. 7 The 3- and 5-year survival rates among patients without coronary artery disease were 71% compared with 58% and 29%, respectively, among patients with coronary artery disease (P NS because of small sample size). This is in contrast to our previous report. 7 The relationship between the number of perioperative and late deaths and the preoperative mean gradient is outlined in Table 5. Symptomatic improvement was noted in most of the survivors of surgery. Thirty patients had functional status noted before and after operation. Of these, 85% were severely symptomatic (NYHA class III or IV) before and only 23% were severely symptomatic after operation (Figure 2): 77% of patients (23 of 30 patients) improved by 1 NYHA functional class at follow-up. Twenty-three patients (77%) were NYHA class I or II at follow-up. The year and urgency of operation as well as a history of coronary artery bypass graft surgery or myocardial infarction did not significantly affect survival in this series. Additional factors, including age, sex, preoperative EF, aortic valve area (AVA), cardiac output, mean aortic gradient, prosthesis size, and aortic annular patch enlargement, were not related to survival. Postoperative EF EF was assessed echocardiographically in 93% of the 30-day survivors (38 of 41 patients) at a mean interval of 18 months after operation. Of the patients in whom LVEF was assessed after operation, 28 (74%) showed a positive change. The mean change was an increase of EF units (P 0.001) (mean preoperative EF, 24 7%; mean postoperative EF, 32 14%) (Figure 3). The postoperative EF ranged from 12% to 65%. AVA was significantly related to a change in EF after operation (P 0.03) (r 0.36). Sex was significantly related to postoperative EF (P 0.009); women had higher postoperative EF. There was no significant preoperative sex difference in EF. Discussion In severe aortic stenosis, the left ventricle compensates for chronic pressure overload by hypertrophy in an attempt to normalize wall stress. Initially, EF and cardiac output are maintained. When wall stress exceeds the compensating mechanism, LV systolic function declines secondary to afterload mismatch, and the mean pressure gradient generated by the LV may be low despite the presence of severe aortic TABLE 5. Data on Perioperative and Late Deaths Related to Mean Gradient Preop MG, mm Hg Patients, n Periop Deaths, n Late Deaths, n MG indicates mean gradient. Figure 3. Comparison of preoperative (preop) and postoperative (postop) LVEF. Solid horizontal line indicates mean EF; hatched box, 1 SD; and vertical line, highest and lowest mean values.

5 1944 Circulation April 25, 2000 stenosis. Thus, when LV dysfunction is due to afterload mismatch, 4 as seen in severe aortic stenosis, aortic valve replacement results in improvement in EF symptoms and survival. 7 LV function and mean aortic valve gradient are prognostic indicators of outcome among patients undergoing aortic valve replacement for aortic stenosis. 18 However, the outcome of aortic valve replacement among patients with LV dysfunction and low transvalvular mean gradient has not been well characterized. These patients represent the most controversial and clinically challenging patients with aortic stenosis. Two series reported the outcome of aortic valve replacement in patients with low transvalvular pressure gradient. 19,20 However, these 2 series combined described only 22 patients with transvalvular mean gradient 30 mm Hg, and no EF data were reported for 14 of them. When our present series was compared with the 125 patients with aortic stenosis and reduced LVEF but mean gradient 30 mm Hg previously reported, 7 there was a significant difference in survival (P 0.04) (Figure 1B). Thus, we undertook to define the outcome and to further stratify risk in this group of patients. The paucity of data on the outcome of aortic valve replacement in patients with aortic stenosis and LV dysfunction with low mean gradient led us to review 52 such patients in an attempt to determine perioperative mortality, overall survival, and predictors of outcome. By multivariate analysis, we found that 30-day mortality was related to aortic prosthesis size. All patients had LV dysfunction and low mean gradient; therefore, further EF and mean gradient analysis alone were not related to survival. Improved postoperative EF was related to preoperative AVA and female sex. In the present study, smaller aortic prosthesis size was associated with increased surgical mortality, as previously reported. 18 This remained an important predictor of perioperative survival even though 17% had undergone simultaneous aortic root enlargement to allow placement of a larger prosthesis. Of the 11 patients who died perioperatively, 5 received an aortic prosthesis 23 mm. There was no relationship between body surface area and perioperative mortality, but small prosthesis size reflects small annulus dimension. The body surface area of the patient who received the 17-mm aortic prosthesis was 1.32 m 2, and the mean SD of body surface area of the 3 patients who received 19-mm prostheses was m 2. Small valve prostheses have higher transvalvular gradients than larger prostheses. 21,22 The failure to decrease afterload effectively with smaller aortic prostheses in these patients with low preoperative mean transvalvular gradient may influence surgical outcome. The problem of valve-prosthesis patient mismatch is also potentially important regarding this series of patients. The effective orifice area of a prosthesis is less than that of a normal human valve. Occasionally, the reduced prosthetic valve area further confounds the clinical situation, resulting in symptomatic and hemodynamic deterioration. This occurs when the decrease in afterload is less than expected because of small prosthesis size. This may account, in part, for the increased mortality noted among patients with the smallest prostheses. 23,24 Small aortic prostheses have also been associated with increased late mortality among patients undergoing simultaneous coronary artery bypass graft surgery. 25 This association was not appreciated among the patients we report. It remains uncertain whether annular enlargement 26 to accommodate a prosthesis 1 or 2 sizes larger will improve mortality. Effect of Aortic Valve Replacement on Postoperative EF Aortic valve replacement for aortic stenosis decreases ventricular afterload. 27 EF is expected to improve after aortic valve replacement among patients with severe aortic stenosis and decreased preoperative EF. 5,6,27,28 Those who do not improve probably have permanent myocardial fibrosis. Previous studies showed that decreased preoperative EF, previous myocardial infarction, and low preoperative aortic valve gradient are associated with decreased postoperative EF. 29 An improvement in postoperative LVEF of 10 EF units (Figure 3) was noted in our study. The relationship of sex differences in LV adaptation to aortic stenosis has been described A substantial sex-associated difference in regression of LV adaptation to chronic pressure and volume overload has also been reported. 18 The factors accounting for these sex differences have not been characterized. The sex difference in our series (improved postoperative EF in women) was an isolated sex-related finding (ie, preoperative EF and mean gradient were not significantly different between men and women). Excessive hypertrophy has been reported in some patients with aortic stenosis. 31,32 This finding was not noted among the 52 patients reported in this series. Smaller preoperative AVA was significantly related to a change in postoperative EF. The smaller preoperative AVA may suggest a more severe degree of aortic stenosis in these patients with low preoperative mean gradient. Preoperative identification of appropriate surgical candidates may be improved by the use of dobutamine infusion 33 and/or transesophageal imaging. 34 These modalities may aid in optimizing surgical and overall survival. An important variable that we were unable to assess was the true degree of aortic valve stenosis. Estimation of AVA in patients with low cardiac output and low transvalvular gradient is difficult, and in several patients in this series, the surgeon noted less than severe aortic stenosis at operation. Thus, some patients may have had another cause for LV dysfunction in conjunction with aortic valve stenosis of moderate severity. In our current practice, we use dobutamine during hemodynamic assessment; however, this was not performed in a sufficient number to allow risk stratification in the current series. Limitations Lack of Power This series has limited power to stratify risk and identify statistical predictors of outcome. However, no larger series of such patients is available in the literature.

6 Connolly et al Aortic Valve Replacement 1945 Follow-Up The postoperative EF was determined for 93% of survivors of surgery (38 of 41 patients). This should be considered in the interpretation of results, because the performance of echocardiography may have been an indicator for better outcome. Comparison of baseline characteristics between survivors with and without determination of postoperative EF indicated no differences in proportion of female patients, preoperative NYHA functional class, age, and percentage of patients with coronary artery disease in this assessment. EF Analysis Echocardiographic estimates of LVEF may be a cause for concern; the use of echocardiography in this clinical setting, however, is standard clinical practice. Previous studies from our institution and others have documented acceptable correlations with angiography 35 and have confirmed reproducibility Other Causes of LV Dysfunction Causes of LV dysfunction related to factors other than aortic stenosis and coronary artery disease cannot be excluded in this patient population. Lack of Control Group All of the patients included in this study underwent aortic valve replacement; thus, the clinical dilemma of differentiating LV systolic dysfunction due to aortic stenosis from moderate aortic stenosis with a coexistent cardiomyopathic process cannot be addressed. Cardiac Output Determination Cardiac output determination may be unreliable when measured by the thermodilution technique, particularly in lowoutput states. In our series, however, only 6 of the 50 patients in whom cardiac output was measured (12%) had measurement by thermodilution, so this technique should not have adversely affected our data. Dobutamine Hemodynamic Assessment Intravenous administration of dobutamine has been proposed as a method to determine surgical outcome in patients with low-output low-gradient aortic stenosis, when there is uncertainty about the severity of aortic stenosis. 33 Hemodynamic evaluation during dobutamine infusion was not performed in enough patients to allow risk stratification in this series. Conclusions Patients with low-gradient aortic stenosis represent a small but controversial subset. In our patients with decreased LVEF, low mean gradient, advanced age, and high prevalence of coronary artery disease, surgical mortality was lower than previously reported and was related to aortic prosthesis size and patient age. The early and intermediate follow-up results are acceptable compared with those of age- and sex-matched controls. Marked improvement in symptoms and LVEF occurred in 70% of the survivors. 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