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Predictor of left ventricular dysfunction after aortic valve replacement in mixed aortic valve disease
International Journal of Cardiology 228 (2017) 511–517
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International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Predictor of left ventricular dysfunction after aortic valve replacement in mixed aortic valve disease Alexander C. Egbe, Carole A. Warnes ⁎ Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA
a r t i c l e
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Article history: Received 2 July 2016 Received in revised form 5 November 2016 Accepted 10 November 2016 Available online 14 November 2016 Keywords: Left ventricle dysfunction Mixed aortic valve disease Left ventricular mass Aortic valve replacement
a b s t r a c t Background: The fate of the left ventricle (LV) after aortic valve replacement (AVR) in mixed aortic valve disease (MAVD) is unknown. Methods: Patients with moderate-severe MAVD, ejection fraction ≥50%, and no coronary artery disease who underwent AVR were identified. Moderate-severe MAVD was defined as a combination of ≥moderate aortic stenosis and ≥moderate aortic regurgitation. Assessment for LVD was performed at 1 and 5 years after AVR. The purpose of the study was to determine prevalence and predictors of early and late left ventricular dysfunction (LVD) defined as ejection fraction b50% at 1 and 5 years post-AVR. The severity of LV hypertrophy was assessed using LV mass index (LVMI), while relative wall thickness (RWT) was used to determine the type of hypertrophy. RWT was calculated as (2 × posterior wall thickness) / LV end-diastolic dimension (LVEDD). A RWT score ≥0.42 and b 0.42 indicates concentric and eccentric hypertrophy respectively. Results: Patients with MAVD (n = 179); age 63 ± 8 years, males 134 (75%); underwent AVR at Mayo Clinic, 1994–2010. Early LVD occurred in 38(21%). Predictors of early LVD were LVMI/LVEDD N3.1 (HR 1.83, CI 1.59– 1.98); RWT N0.46 (HR 2.16, CI 1.21–4.99); and older age (HR 1.62, CI 1.23–3.02). Assessment of LV function was performed in 124 patients at 5-years post-AVR, and late LVD was present in 29(23%). Predictors of late LVD were LVMI/LVEDD N3.1 (HR 1.77, CI 1.24–2.01) and RWT N0.46 (HR 1.65, CI 1.29–2.24). All-cause mortality occurred in 21(12%), and was more common in patients with LVMI/LVEDD N3.1 (P = 0.043) and RWT N 0.46 (P = 0.029). Patients with postoperative LVD showed less regression of LV mass after AVR even after controlling for blood pressure. Conclusions: LVD can occur after AVR even in the setting of normal preoperative LV function and absence of coronary artery disease. Preoperative LV mass was predictive of LVD and should be taken into consideration when determining the timing of AVR. © 2016 Elsevier Ireland Ltd. All rights reserved.
1. Introduction The goal of aortic valve replacement (AVR) is to relieve symptoms, prolong life and halt progression of left ventricular dysfunction (LVD) [1–5]. The Valvular Heart Disease guidelines recommended AVR in symptomatic severe aortic stenosis (peak velocity N 4 m/s or mean gradient N40 mm Hg or valve area b 1.0 cm2), or in the setting of reduced left ventricular (LV) ejection fraction, and in symptomatic severe aortic regurgitation with LV end systolic dimension N 50 mm and LV ejection fraction b50% [6,7].
Abbreviations: AVR, Aortic valve replacement.; LV, Left ventricle; LVD, Left ventricular dysfunction; LVMI, Left ventricular mass index; MAVD, Mixed aortic valve disease; RWT, Relative wall thickness. ⁎ Corresponding author at: Division of Cardiovascular Diseases, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. E-mail addresses: [email protected] (A.C. Egbe), [email protected] (C.A. Warnes).
http://dx.doi.org/10.1016/j.ijcard.2016.11.237 0167-5273/© 2016 Elsevier Ireland Ltd. All rights reserved.
There are limited data about mixed aortic valve disease (MAVD) and as a result a common practice is to determine the optimal timing of AVR in MAVD using the guideline criteria for isolated aortic stenosis or regurgitation [8,9]. The fate of the LV after AVR in moderate-severe MAVD is unknown, and the purpose of this study is to determine the prevalence and predictors of LVD in this population. 2. Methods 2.1. Patient selection This is a retrospective review of all adult patients (age N 18 years) with moderatesevere MAVD that underwent AVR at Mayo Clinic from January 1994 to December 2010. The patients were identified from the electronic medical record using free text search software (Advanced Cohort Explorer), and the Mayo Clinic Institutional Review Board approved this study protocol. Moderate-severe MAVD was defined as the combination of ≥moderate aortic stenosis and ≥moderate aortic regurgitation. Normal LV systolic function (ejection fraction ≥50%) and at least 2-year clinical and echocardiographic follow-up were required for inclusion in the study. Loss of follow-up was defined as no clinical follow up in 2 years.
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The patients with radiation-induced valvular heart disease, prior endocarditis, cardiomyopathy, prior aortic valve intervention, coronary artery disease, and co-existent valvular heart disease defined as moderate or greater stenosis or regurgitation of the mitral, tricuspid or pulmonary valves were excluded. Coronary artery disease was defined as history of myocardial infarction, angioplasty, coronary artery bypass grafting, or coronary artery stenosis documented on angiography. The final cohort comprised 179 patients. Fig. 1 shows cohort selection.
2.2. Data collection and study design Clinical, echocardiographic, and surgical data were abstracted from medical records. The presence of atrial fibrillation and hypertension at the 1-year and 5-year clinic visits were documented. Atrial fibrillation was considered to be present if documented on electrocardiogram, Holter monitor or device interrogation within 6 months of clinic visit. Our definitions for clinical data were the same as used in prior studies [9]. The purpose of the study was to determine the prevalence and predictors of early and late LVD. Early was defined as LV ejection fraction b50% at 1 year after AVR while late LVD was defined as LV ejection fraction b50% at 5 years after AVR. Assessment of LV function was performed at baseline (before AVR), at 1 year and at 5 years after AVR. Only transthoracic echocardiograms performed within 3 months prior to AVR; at 1 ± 0.3 years after AVR; and at 5 ± 1 years after AVR were selected for analysis.
2.3. Echocardiography According to published guidelines [10–12], moderate aortic stenosis was defined as a peak aortic velocity of 3.0–3.9 m/s and valve area 1.1–1.5 cm2; severe aortic stenosis as peak velocity ≥4.0 m/s and valve area ≤1.0 cm2; moderate aortic regurgitation as a combination of at least 2 of the following: vena contracta 0.3–0.6 cm, regurgitant volume 30–59 ml/beat, effective regurgitant orifice area 0.10–0.29 cm2, and angiographic grade 2+ regurgitation; severe aortic regurgitation as a combination of at least 2 of the following: vena contracta N0.6 cm, regurgitant volume N60 ml/beat, effective regurgitant orifice area N0.3 cm2; angiographic grade 3+/4+ regurgitation, and the presence of holodiastolic flow reversal in abdominal aorta. For this study, the moderate-severe MAVD cohort comprised patients that met both velocity and valve area criteria for aortic stenosis, and at least 2 of the criteria for aortic regurgitation. The left ventricular mass index (LVMI), relative wall thickness (RWT) and ejection fraction were calculated by 2-dimensional echocardiography; the left atrial volume index was calculated by area-length or biplane methods [13,14]. An increase in LVMI indicates LV hypertrophy while RWT determines the type of hypertrophy. RWT is calculated as (2 × LV posterior wall thickness)/LV end-diastolic dimension, and these measurements were derived from 2 dimensional echocardiography. A RWT score ≥0.42 and b0.42 indicates concentric and eccentric hypertrophy respectively base on the current American Society of Echocardiography guidelines [14]. Diastolic dysfunction was defined as the presence of grade III diastolic dysfunction as documented in the echocardiogram report. Grade III diastolic dysfunction indicates restrictive LV filling characterized by a short mitral inflow deceleration time b150 msec, increased mitral inflow E/A ratio N2.0, elevated E/E′ N14, and left atrial volume N34 ml/m2 [15]. Prosthetic valve dysfunction was defined as mean gradient N25 mm Hg or pressure half time N100 msec, and/or the presence of ≥moderate aortic regurgitation. Moderate patient-prosthesis mismatch was defined as an effective orifice area index of 0.65– 0.85 cm2/m2) while severe patient-prosthesis mismatch was defined as an effective orifice area index b0.65 cm2/m2 [16].
2.4. Statistical analysis All statistical analysis was performed using JMP version 11.0 software (SAS Institute Inc., Cary, NC, USA). Categorical variables were expressed as percentages while continuous variables were expressed as mean ± standard deviation or median (interquartile range, IQR) for skewed data. Comparison of categorical variables was performed using Chisquare test or Fisher exact test, while comparison of continuous variables was performed with two-sided unpaired Student t-test or Wilcoxon rank sum test as appropriate. Cox proportional-hazard models were used to determine predictors of LVD, and expressed as hazard ratio (HR) and 95% confidence interval (CI). We included aortic valve parameters, LV function and thickness parameters, and clinical risk factors in the univariable model. Only the variables significant in the univariable model (P b 0.05) were included in the Cox multivariable model. The occurrence of LVD was assessed using the Kaplan-Meier method, and compared by using the log-rank test. The time of AVR was considered as the time zero for this analysis. Only patients without documented acute coronary syndrome were included in this analysis. P values b0.05 were considered significant.
3. Result 3.1. Baseline characteristics There were 179 patients (mean age 63 ± 8 years, males 134 [75%]) with moderate-severe MAVD that underwent AVR within the study period. A bioprosthetic valve was implanted in 77 (43%) and concomitant aorta replacement was performed in 39 (22%). Postoperative complications include temporary support with intra-aortic balloon pump (n = 1), early reoperation for bleeding (n = 3) and temporary pacing for transient heart block (n = 1). The indication for AVR was due to symptoms in 158 (88%) and abnormal exercise test in 19 (12%) patients. The baseline characteristics of the cohort are shown in Table 1. At the time of hospital dismissal after AVR, 2 patients (1%) had moderate patientprosthesis mismatch and no patient had severe patient-prosthesis mismatch. 3.2. Prevalence and predictors of early LVD All patients had clinical and echocardiographic evaluation at 1 year after AVR. Early LVD was present in 38 (21%) and 2 (1%) had ejection fraction b40%. None of these patients had a documented acute coronary syndrome or angiographic evidence of coronary artery disease from the time of AVR to the time of their 1-year postoperative assessment. There were 8 of 179 patients (4%) with paced rhythm at baseline and at 1-year postoperative assessment of LV function. There were 5 of 179 patients (3%) in atrial fibrillation at baseline, and 7 of 179 patients (4%) in atrial fibrillation at 1-year postoperative assessment. All 7 patients in atrial fibrillation had ventricular rate b100 beats per minute, and only 1 of them had LV ejection fraction b50%. The multivariable predictors of early LVD were LVMI/LVEDD (HR 1.83, CI 1.59–1.98, P = 0.001), RWT N0.46 (HR 2.16, CI 1.21–4.99, P = 0.028); and older age (HR 1.62, CI 1.23–3.02, P = 0.024), Table 2. The presence of atrial fibrillation was not predictive of early LVD. Fig. 2 shows the LV ejection fraction of all 179 patients at 1 year post AVR. A decrease in ejection fraction N 10% occurred in 41 patients (23%). On multivariable analysis, the predictors of N10% decrease in ejection fraction were LVMI/LVEDD (HR 1.69, CI 1.23–2.08, P = 0.021) and RWT N 0.46 (HR 1.79, CI 1.11–3.54, P = 0.041). 3.3. Prevalence and predictors of late LVD
Fig. 1. Top panel: Preoperative cohort selection. There 856 patients with moderate-severe MAVD. The following patients were excluded: patients that met pre-defined exclusion criteria, follow-up b2 years, and patients with preoperative ejection fraction b50%. Bottom panel: Cohort selection from the time of aortic valve replacement, through evaluation at 1 year, and to evaluation at 5 years. There 39 patients excluded in the interval between evaluation at 1 year and 5 years. *Exclusion criteria described in the methods section; FU: follow-up, EF; ejection fraction; echo: echocardiogram.
A 5-year clinical and echocardiographic follow-up was complete in 140/179 (78%). There were 39/179 (31%) without a 5-year follow up for the following reasons: death (n = 21), loss of follow-up (n = 16) and no echocardiogram at 5 years (n = 2). Among the 140 patients with 5-year follow up data, 16 (13%) had an acute coronary syndrome or angiographic documentation of coronary artery disease after AVR. These patients were excluded in the analysis for predictors of late LVD. Late LVD was present 29/124 (23%) and 11 (9%) had an ejection fraction b 40%. Among the 29 patients with late LVD, 24 had early LVD and
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Table 1 Baseline clinical and echocardiographic data. Entire cohort (n = 179)
Normal LV function (n = 141)
Early LVD (n = 38)
P value
Male Age at AVR years Body surface area
134 (75%) 63 ± 8 2.0 ± 0.4
107 (76%) 62 ± 11 2.0 ± 0.4
27 (71%) 64 ± 9 2.0 ± 0.2
0.37 0.49 0.18
Echo data Aortic peak velocity, m/s Aortic mean gradient, mmHg Aortic valve area, cm2 Pressure half time, ms LV ejection fraction, % LVEDD, mm LVESD, mm LV posterior wall thickness, mm LV septal wall thickness, mm LVMI, g/m2 LVMI/LVEDD Relative wall thickness LV diastolic dysfunctiona LA volume index, ml/m2 RV systolic pressure, mm Hg Aortic dimension 46–50 mm Aortic dimension N50 mm
4.5 ± 0.4 47 ± 6 1.14 ± 0.30 296 ± 138 60 ± 4 61 ± 6 38 ± 3 13 ± 2 14 ± 3 181 ± 31 3.0 ± 0.1 0.44 ± 0.02 47 (26%) 34 ± 4 49 (41, 56) 36 (21%) 3 (3%)
4.4 ± 0.6 46 ± 12 1.13 ± 0.21 304 ± 128 60 ± 6 60 ± 4 38 ± 7 13 ± 3 14 ± 2 176 ± 35 2.9 ± 0.1 0.43 ± 0.04 21(22%) 33 ± 7 47(40, 56) 29 (21%) 2 (2%)
4.5 ± 0.7 48 ± 11 1.10 ± 0.19 291 ± 123 59 ± 5 61 ± 7 39 ± 4 14 ± 3 14 ± 2 190 ± 39 3.1 ± 0.2 0.46 ± 0.03 16 (42%) 36 ± 4 54 (50–59) 7 (18%)
0.41 0.39 0.64 0.18 0.09 0.18 0.27 0.19 0.66 0.033 0.008 0.001 0.004 0.037 0.036 0.41
Clinical Bicuspid/Unicuspid valve Rheumatic heart disease Aorta replacement Bioprosthetic valve Atrial fibrillation Diabetes Active smoking Creatinine clearance b60 ml/min Hypertension Hyperlipidemia
61 (34%) 21 (12%) 39 (22%) 77 (43%) 29 (16%) 21 (12%) 22 (12%) 17 (10%) 153(63%) 83(38%)
49 (35%) 16 (11%) 32 (22%) 60 (43%) 16 (11%) 17 (12%) 16 (11%) 13 (9%) 111(60%) 59(38%)
12 (32%) 5 (13%) 7 (18%) 17 (45%) 13 (34%) 4 (11%) 6 (16%) 4 (11%) 42(72%) 24(41%)
0.61 0.82 0.17 0.39 b0.0001 0.32 0.082 0.13 0.01 0.45
AVR: Aortic valve replacement. LA: Left atrium. LV: Left ventricle. LVEDD: Left ventricular end-diastolic dimension. LVESD: Left ventricular end-systolic dimension. LVMI: Left ventricular mass index. RV: Right ventricle. a LV diastolic dysfunction: Only 151 had diastolic assessment at baseline.
never recovered LV function while the other 5 had normal LV function at 1 year follow up but developed LVD afterwards. The clinical characteristics of these 5 patients with late onset LVD did not differ from the rest of the cohort. The multivariable predictors of late LVD were LVMI/LVEDD
N3.1 (HR 1.77, CI 1.24–2.01, P = 0.031) and RWT N0.46 (HR 1.65, CI 1.29–2.24, P = 0.014), Table 3. Fig. 2 shows the LV ejection fraction of all 124 patients at 5 years post AVR. Compared to the baseline ejection fraction prior to AVR, a decrease in ejection fraction N10% occurred in
Table 2 Predictors of Early LVD. Univariable
Age (per 10 year increase) Aortic peak velocity, m/s Pressure half time, ms LV ejection fraction N60% LVEDD, mm LVESD, mm LA volume index N35 ml/m2 LVMI (per 10 g/m3 increase) LVMI/LVEDD N3.1 Relative wall thickness N 0.46 Atrial fibrillationa Unicuspid/bicuspid valve Diabetes Hypertensionb Rheumatic heart disease
Multivariable
HR (95% CI)
P value
HR (95% CI)
P value
3.91 (2.61–4.21) 1.91 (2.61–4.21) 1.33 (0.86–2.32) 0.86 (0.46–1.19) 1.66 (0.26–4.17) 1.52 (0.71–2.19) 1.11 (0.33–2.81) 1.29 (1.08–1.78) 2.51 (1.02–3.12) 2.12 (1.53–3.94) 1.51 (0.63–2.44) 0.61(0.32–1.09) 1.55 (0.82–2.14) 1.38 (0.48–2.17) 1.05 (0.32–2.14)
0.001 0.007 0.42 0.092 0.31 0.39 0.44 0.012 0.016 0.007 0.26 0.081 0.093 0.091 0.24
1.62 (1.23–3.02) 2.12 (0.67–4.56)
0.024 0.16
1.34 (0.67–1.53) 1.83 (1.59–1.98) 2.16 (1.21–4.99)
0.37 0.001 0.028
HR: Hazard ratio. CI: Confidence interval. a Atrial fibrillation: documented atrial fibrillation within 6 months of clinic visit at 1-year post AVR. b Hypertension: systolic blood pressure N 140 mm Hg at clinic visit at 1-year post AVR.
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32 patients (26%). On multivariable analysis, the only predictor of N 10% decrease in ejection fraction at 5 years post AVR was RWT N0.46 (HR 1.85, CI 1.26–4.17, P = 0.034). The 16 patients with documented acute coronary syndrome were excluded from survival-free from LVD analysis. For the 164 patients included in the analysis, the prevalence of LVD was 16%, 21% and 23% at 1, 3 and 5 years respectively (Fig. 3).
3.4. Aortic valve prostheses There were 16 patients that had prosthetic valve dysfunction, and the presence of prosthetic dysfunction was not predictive of LVD. The mean gradient and effective orifice area at 1 year post AVR were 16 ± 3 mm Hg and 2.16 ± 0.25 cm2, while the mean gradient and effective orifice area at 5 years post AVR were 21 ± 4 mm Hg and 1.82 ± 0.41 cm2.
3.5. Death There were 21 deaths (10 cardiac, 9 non-cardiac, and 2 unknown) reported during the study period. The causes of death were congestive heart failure (n = 3); myocardial infarction (n = 2), endocarditis (n = 2), sudden death (n = 2), mechanical aortic prosthetic thrombosis (n = 1), stroke (n = 2), cancer (n = 4), sepsis (n = 1), renal failure (n = 2), and unknown cause (n = 2). For the patients that died, the median survival from the time of AVR was 2 years (IQR: 1–3). All-cause mortality was higher in patients with LVMI/LVEDD N 3.1 (P = 0.043) and RWT N 0.46 (P = 0.029, Fig. 4.
3.6. LV reverse remodeling An analysis of the trend in LVMI and RWT was performed for the 124 patients with 5-year follow-up and absence of coronary artery disease. The patients with late LVD had higher preoperative LVMI/LVEDD and RWT (3.1 ± 0.2 and 0.46 ± 0.03 vs 2.9 ± 0.1 and 0.43 ± 0.04, P b 0.008); at 1 year after AVR (3.1 ± 0.3 and 0.45 ± 0.03 vs 2.8 ± 0.2 and 0.41 ± 0.03, P b 0.003) and at 5 years after AVR (3.0 ± 0.2 and 0.44 ± 0.03 vs 2.7 ± 0.1 and 0.40 ± 0.02, P b 0.001). The patients with postoperative LVD also showed less regression of LV mass after AVR even after controlling for blood pressure, Fig. 4. 4. Discussion This is a retrospective review of 179 patients with moderate-severe MAVD to determine the prevalence and predictors of LVD after AVR. These are the main findings: 1) The prevalence of early and late LVD was 21% and 23% respectively, and the risk factors for LVD were older age and higher preoperative LV mass; 2) The patients with LVD has less LV reverse remodeling after AVR; 3) Higher preoperative LV mass was associated with all-cause mortality. 4.1. Prevalence of LVD This study reviewed the outcome of AVR in 179 patients with moderate-severe MAVD, normal LV function and no documented coronary artery disease. LVD was identified in 21% and 23% of the cohort at 1 and 5 years after AVR respectively. The current guideline recommendations for AVR are based on studies that showed excellent survival and preservation of LV function when AVR is performed prior to the onset of LVD in patients with isolated severe aortic stenosis or regurgitation [1–5,17–20] There are no guideline recommendations for the timing of AVR in MAVD, and as a result, a common practice is to apply the recommendations for the predominant lesion. The current study shows that LVD occurred in one-fifth of the patients with moderate-severe MAVD who underwent AVR, at the “appropriate time” based on the criteria for isolated aortic stenosis or regurgitation. This study identified older age and higher preoperative LV mass as risk factors for LVD. A large retrospective study of 4264 patients that underwent AVR for isolated or mixed lesions also showed that severe LV hypertrophy was the strongest predictor of LVD and death after AVR [21]. One-third of that cohort had MAVD and the severity of preoperative LV hypertrophy was higher in the MAVD subgroup compared to the patients with isolated aortic stenosis or regurgitation. It is important to note that coronary artery disease was present in 66% of that cohort making it difficult to determine if LVD was due to valvular heart disease or coronary artery disease. Additionally, one-quarter of that cohort had LVD prior to AVR. In contrast, the current study excluded patients with coronary artery disease and preoperative LVD thereby eliminating or at least minimizing these confounders. Notwithstanding, higher preoperative LV mass (LVMI/LVEDD N 3.1 and RWT N 0.46) was also identified as a predictor of LVD similar to the report by Beach and colleagues [21]. Several other studies have also reported an association between severe LV hypertrophy and cardiovascular adverse events in patients with isolated aortic stenosis [22–24]. 4.2. Combined pressure-volume load
Fig. 2. Bar chart showing the spectrum of LV ejection fraction a 1 year post AVR (top panel) and 5 years post AVR (bottom panel).
A major pitfall of determining the timing of AVR in MAVD based on the criteria for isolated lesion is the inherent assumption that the hemodynamic impact of combined pressure and volume load on the LV is not remarkably different from that of isolated pressure or volume load. Studies have shown that this assumption may not be correct [25,26]. Lamb and colleagues [25] showed that the ratio of LVMI/LV end diastolic volume decreased in patients with aortic stenosis but increased in
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Table 3 Predictors of Late LVD. Univariable
Age (per 10 year increase) Aortic peak velocity, m/s Prosthetic dysfunctiona Pressure half time, ms LV ejection fraction N60% LVEDD, mm LVESD, mm LA volume index N35 ml/m2 LVMI (per 10 g/m3 increase) LVMI/LVEDD N3.1 Relative wall thickness N0.46 Atrial fibrillationb Unicuspid/bicuspid valve Diabetes Hypertensionc Rheumatic heart disease a b c
Multivariable
HR (95% CI)
P value
2.27 (0.87–4.71) 1.55 (0.46–2.13) 1.23 (0.84–2.07) 2.12 (0.13–4.94) 1.33 (0.16–3.53) 3.81 (0.25–5.26) 1.29 (0.68–1.78) 2.53 (0.72–4.02) 1.51 (1.12–2.35) 1.94 (1.19–2.83) 2.55 (1.82–4.14) 3.25 (0.59–5.33) 1.01(0.62–2.13) 1.27 (0.87–1.71) 1.86 (1.14–2.15) 1.23 (0.14–3.07)
0.43 0.13 0.18 0.32 0.17 0.18 0.39 0.29 0.011 0.027 0.001 0.21 0.29 0.18 0.005 0.33
HR (95% CI)
P value
1.33 (0.42–1.84) 1.77 (1.24–2.01) 1.65 (1.29–2.24)
0.082 0.031 0.014
1.43 (0.55–2.14)
0.087
Prosthetic dysfunction: mean gradient N25 mm Hg or presence of ≥moderate regurgitation. Atrial fibrillation: documented atrial fibrillation within 6 months of clinic visit at 5-year post AVR. Hypertension: systolic blood pressure N140 mm Hg at clinic visit at 5-year post AVR.
patients with aortic regurgitation after AVR. AVR resulted in an improvement in diastolic function in the patients with aortic stenosis but worsening of diastolic function in the patients with aortic regurgitation in that series [25]. Similarly, another study comparing LV mass in 71 patients undergoing AVR showed that LVMI decreased in the patients with aortic stenosis but did not change significantly in the patients with aortic regurgitation [26]. These studies show that the LV response to pressure load and remodeling after AVR, differed from volume load and remodeling after AVR. It is therefore unrealistic to assume that the hemodynamic response of combined pressure and volume load will conform to the pattern of isolated pressure or volume load. Concentric LV hypertrophy is an adaptive mechanism characterized by parallel replication of new sarcomeres resulting in increased wall thickness and normalization of wall stress [27,28]. However severe LV hypertrophy can become “mal-adaptive” resulting in LV dysfunction and major adverse cardiovascular events [21–24,29]. Although, the exact mechanism resulting in adverse events is unclear, some data suggests that this may due to fibrosis resulting from a mismatch between myocardial blood supply and demand in the setting of severe LV hypertrophy [30]. There are emerging data about the use of T1 mapping technique in cardiac magnetic resonance imaging to quantify severity of fibrosis and perhaps improve risk stratification [30,31]. The goal of AVR is to prevent LVD and prolong life. All the patients in this study underwent AVR at the appropriate time based on the guideline
criteria for isolated aortic stenosis or regurgitation, and the yet some of these patients already had severe and mal-adaptive LV hypertrophy at the time of AVR. The cohort had normal preoperative LV ejection fraction, which is a load dependent index of LV contractility. Perhaps some of the patients already had decreased LV contractility prior to AVR, and this was masked by complex loading conditions present in MAVD. Are we operating too late? A different study design will be required to determine if mal-adaptive LV hypertrophy and subsequent LVD can be prevented by performing AVR earlier in patients with MAVD. Although the current study does not provide data about the optimal timing for AVR in this population, the authors showed that waiting until the occurrence of severe LV hypertrophy was associated with postoperative LVD and all-cause mortality. The patients with postoperative LVD showed less regression of LV mass after AVR even after controlling for blood pressure. 4.3. Limitations This study is based on a selected cohort of patients that survived for at least 2 years after AVR and the prevalence of LVD observed in this study may not be representative of all MAVD patients undergoing AVR. It is logical to anticipate that LVD may be more common than reported in this study because the patients that died perioperatively were excluded from this study. Although this study excluded the patients with coronary artery disease and also controlled for blood pressure and atrial fibrillation at the time of clinic visit, other confounders may have influenced the results because of the retrospective study design. The indications for AVR in these patients were symptoms and abnormal exercise test but the investigators were unable to accurately determine the time interval from onset of symptoms to AVR. Lastly, all-cause mortality in this study might be under-estimated because mortality data were abstracted from electronic medical records. However, this does not influence the finding that all-cause mortality was higher in patients with higher preoperative LV mass. 5. Conclusion
Fig. 3. Kaplan Meier curve showing the occurrence of LVD Out of the 179 patients enrolled in the study, only 163 patients without documented acute coronary syndrome were included in the analysis. LVD: left ventricular dysfunction, AVR: aortic valve replacement.
One-fifth of patients with moderate-severe MAVD and normal LV function develop LVD after AVR even in the absence of coronary artery disease. The severity of LV hypertrophy was associated with postoperative LVD and all-cause mortality. This study emphasizes the difference in the pathophysiology of MAVD compared to isolated aortic stenosis or regurgitation, and also highlights the paucity of evidence-based recommendation to guide
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Fig. 4. Top panel: Regression of left ventricular mass after aortic valve replacement (A) Comparison of regression of LVMI/LVEDD ratio between the patients with LVD (blue) and the patients without LVD (red). (B) Comparison of regression of RWT between the patients with LVD (blue) and the patients without LVD (red). Bottom panel: Comparison of the occurrence of LVD and all-cause mortality by preoperative left ventricular mass (A) Comparison of percentage of patients with early LVD (blue), late LVD (red) and death (green) between the patients with LVMI/LVEDD ratio ≤3.1 vs N3.1 (B) Comparison of percentage of patients with early LVD (blue), late LVD (red) and death (green) between patients with RWT ≤0.46 vs N0.46 LV: Left ventricle; LVD: Left ventricular dysfunction; LVMI: Left ventricular mass index; LVEDD: Left ventricular end diastolic dimension; RWT: Relative wall thickness.
management in this population. Perhaps LV mass should be considered in determining the timing of AVR, in addition to current criteria of symptoms and ejection fraction. A prospective study is required to validate these findings.
[7] [8]
Funding [9]
None. [10]
Conflict of interest None. [11]
Disclosures No relationships with industry. [12]
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International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Predictor of left ventricular dysfunction after aortic valve replacement in mixed aortic valve disease Alexander C. Egbe, Carole A. Warnes ⁎ Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA
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Article history: Received 2 July 2016 Received in revised form 5 November 2016 Accepted 10 November 2016 Available online 14 November 2016 Keywords: Left ventricle dysfunction Mixed aortic valve disease Left ventricular mass Aortic valve replacement
a b s t r a c t Background: The fate of the left ventricle (LV) after aortic valve replacement (AVR) in mixed aortic valve disease (MAVD) is unknown. Methods: Patients with moderate-severe MAVD, ejection fraction ≥50%, and no coronary artery disease who underwent AVR were identified. Moderate-severe MAVD was defined as a combination of ≥moderate aortic stenosis and ≥moderate aortic regurgitation. Assessment for LVD was performed at 1 and 5 years after AVR. The purpose of the study was to determine prevalence and predictors of early and late left ventricular dysfunction (LVD) defined as ejection fraction b50% at 1 and 5 years post-AVR. The severity of LV hypertrophy was assessed using LV mass index (LVMI), while relative wall thickness (RWT) was used to determine the type of hypertrophy. RWT was calculated as (2 × posterior wall thickness) / LV end-diastolic dimension (LVEDD). A RWT score ≥0.42 and b 0.42 indicates concentric and eccentric hypertrophy respectively. Results: Patients with MAVD (n = 179); age 63 ± 8 years, males 134 (75%); underwent AVR at Mayo Clinic, 1994–2010. Early LVD occurred in 38(21%). Predictors of early LVD were LVMI/LVEDD N3.1 (HR 1.83, CI 1.59– 1.98); RWT N0.46 (HR 2.16, CI 1.21–4.99); and older age (HR 1.62, CI 1.23–3.02). Assessment of LV function was performed in 124 patients at 5-years post-AVR, and late LVD was present in 29(23%). Predictors of late LVD were LVMI/LVEDD N3.1 (HR 1.77, CI 1.24–2.01) and RWT N0.46 (HR 1.65, CI 1.29–2.24). All-cause mortality occurred in 21(12%), and was more common in patients with LVMI/LVEDD N3.1 (P = 0.043) and RWT N 0.46 (P = 0.029). Patients with postoperative LVD showed less regression of LV mass after AVR even after controlling for blood pressure. Conclusions: LVD can occur after AVR even in the setting of normal preoperative LV function and absence of coronary artery disease. Preoperative LV mass was predictive of LVD and should be taken into consideration when determining the timing of AVR. © 2016 Elsevier Ireland Ltd. All rights reserved.
1. Introduction The goal of aortic valve replacement (AVR) is to relieve symptoms, prolong life and halt progression of left ventricular dysfunction (LVD) [1–5]. The Valvular Heart Disease guidelines recommended AVR in symptomatic severe aortic stenosis (peak velocity N 4 m/s or mean gradient N40 mm Hg or valve area b 1.0 cm2), or in the setting of reduced left ventricular (LV) ejection fraction, and in symptomatic severe aortic regurgitation with LV end systolic dimension N 50 mm and LV ejection fraction b50% [6,7].
Abbreviations: AVR, Aortic valve replacement.; LV, Left ventricle; LVD, Left ventricular dysfunction; LVMI, Left ventricular mass index; MAVD, Mixed aortic valve disease; RWT, Relative wall thickness. ⁎ Corresponding author at: Division of Cardiovascular Diseases, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. E-mail addresses: [email protected] (A.C. Egbe), [email protected] (C.A. Warnes).
http://dx.doi.org/10.1016/j.ijcard.2016.11.237 0167-5273/© 2016 Elsevier Ireland Ltd. All rights reserved.
There are limited data about mixed aortic valve disease (MAVD) and as a result a common practice is to determine the optimal timing of AVR in MAVD using the guideline criteria for isolated aortic stenosis or regurgitation [8,9]. The fate of the LV after AVR in moderate-severe MAVD is unknown, and the purpose of this study is to determine the prevalence and predictors of LVD in this population. 2. Methods 2.1. Patient selection This is a retrospective review of all adult patients (age N 18 years) with moderatesevere MAVD that underwent AVR at Mayo Clinic from January 1994 to December 2010. The patients were identified from the electronic medical record using free text search software (Advanced Cohort Explorer), and the Mayo Clinic Institutional Review Board approved this study protocol. Moderate-severe MAVD was defined as the combination of ≥moderate aortic stenosis and ≥moderate aortic regurgitation. Normal LV systolic function (ejection fraction ≥50%) and at least 2-year clinical and echocardiographic follow-up were required for inclusion in the study. Loss of follow-up was defined as no clinical follow up in 2 years.
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The patients with radiation-induced valvular heart disease, prior endocarditis, cardiomyopathy, prior aortic valve intervention, coronary artery disease, and co-existent valvular heart disease defined as moderate or greater stenosis or regurgitation of the mitral, tricuspid or pulmonary valves were excluded. Coronary artery disease was defined as history of myocardial infarction, angioplasty, coronary artery bypass grafting, or coronary artery stenosis documented on angiography. The final cohort comprised 179 patients. Fig. 1 shows cohort selection.
2.2. Data collection and study design Clinical, echocardiographic, and surgical data were abstracted from medical records. The presence of atrial fibrillation and hypertension at the 1-year and 5-year clinic visits were documented. Atrial fibrillation was considered to be present if documented on electrocardiogram, Holter monitor or device interrogation within 6 months of clinic visit. Our definitions for clinical data were the same as used in prior studies [9]. The purpose of the study was to determine the prevalence and predictors of early and late LVD. Early was defined as LV ejection fraction b50% at 1 year after AVR while late LVD was defined as LV ejection fraction b50% at 5 years after AVR. Assessment of LV function was performed at baseline (before AVR), at 1 year and at 5 years after AVR. Only transthoracic echocardiograms performed within 3 months prior to AVR; at 1 ± 0.3 years after AVR; and at 5 ± 1 years after AVR were selected for analysis.
2.3. Echocardiography According to published guidelines [10–12], moderate aortic stenosis was defined as a peak aortic velocity of 3.0–3.9 m/s and valve area 1.1–1.5 cm2; severe aortic stenosis as peak velocity ≥4.0 m/s and valve area ≤1.0 cm2; moderate aortic regurgitation as a combination of at least 2 of the following: vena contracta 0.3–0.6 cm, regurgitant volume 30–59 ml/beat, effective regurgitant orifice area 0.10–0.29 cm2, and angiographic grade 2+ regurgitation; severe aortic regurgitation as a combination of at least 2 of the following: vena contracta N0.6 cm, regurgitant volume N60 ml/beat, effective regurgitant orifice area N0.3 cm2; angiographic grade 3+/4+ regurgitation, and the presence of holodiastolic flow reversal in abdominal aorta. For this study, the moderate-severe MAVD cohort comprised patients that met both velocity and valve area criteria for aortic stenosis, and at least 2 of the criteria for aortic regurgitation. The left ventricular mass index (LVMI), relative wall thickness (RWT) and ejection fraction were calculated by 2-dimensional echocardiography; the left atrial volume index was calculated by area-length or biplane methods [13,14]. An increase in LVMI indicates LV hypertrophy while RWT determines the type of hypertrophy. RWT is calculated as (2 × LV posterior wall thickness)/LV end-diastolic dimension, and these measurements were derived from 2 dimensional echocardiography. A RWT score ≥0.42 and b0.42 indicates concentric and eccentric hypertrophy respectively base on the current American Society of Echocardiography guidelines [14]. Diastolic dysfunction was defined as the presence of grade III diastolic dysfunction as documented in the echocardiogram report. Grade III diastolic dysfunction indicates restrictive LV filling characterized by a short mitral inflow deceleration time b150 msec, increased mitral inflow E/A ratio N2.0, elevated E/E′ N14, and left atrial volume N34 ml/m2 [15]. Prosthetic valve dysfunction was defined as mean gradient N25 mm Hg or pressure half time N100 msec, and/or the presence of ≥moderate aortic regurgitation. Moderate patient-prosthesis mismatch was defined as an effective orifice area index of 0.65– 0.85 cm2/m2) while severe patient-prosthesis mismatch was defined as an effective orifice area index b0.65 cm2/m2 [16].
2.4. Statistical analysis All statistical analysis was performed using JMP version 11.0 software (SAS Institute Inc., Cary, NC, USA). Categorical variables were expressed as percentages while continuous variables were expressed as mean ± standard deviation or median (interquartile range, IQR) for skewed data. Comparison of categorical variables was performed using Chisquare test or Fisher exact test, while comparison of continuous variables was performed with two-sided unpaired Student t-test or Wilcoxon rank sum test as appropriate. Cox proportional-hazard models were used to determine predictors of LVD, and expressed as hazard ratio (HR) and 95% confidence interval (CI). We included aortic valve parameters, LV function and thickness parameters, and clinical risk factors in the univariable model. Only the variables significant in the univariable model (P b 0.05) were included in the Cox multivariable model. The occurrence of LVD was assessed using the Kaplan-Meier method, and compared by using the log-rank test. The time of AVR was considered as the time zero for this analysis. Only patients without documented acute coronary syndrome were included in this analysis. P values b0.05 were considered significant.
3. Result 3.1. Baseline characteristics There were 179 patients (mean age 63 ± 8 years, males 134 [75%]) with moderate-severe MAVD that underwent AVR within the study period. A bioprosthetic valve was implanted in 77 (43%) and concomitant aorta replacement was performed in 39 (22%). Postoperative complications include temporary support with intra-aortic balloon pump (n = 1), early reoperation for bleeding (n = 3) and temporary pacing for transient heart block (n = 1). The indication for AVR was due to symptoms in 158 (88%) and abnormal exercise test in 19 (12%) patients. The baseline characteristics of the cohort are shown in Table 1. At the time of hospital dismissal after AVR, 2 patients (1%) had moderate patientprosthesis mismatch and no patient had severe patient-prosthesis mismatch. 3.2. Prevalence and predictors of early LVD All patients had clinical and echocardiographic evaluation at 1 year after AVR. Early LVD was present in 38 (21%) and 2 (1%) had ejection fraction b40%. None of these patients had a documented acute coronary syndrome or angiographic evidence of coronary artery disease from the time of AVR to the time of their 1-year postoperative assessment. There were 8 of 179 patients (4%) with paced rhythm at baseline and at 1-year postoperative assessment of LV function. There were 5 of 179 patients (3%) in atrial fibrillation at baseline, and 7 of 179 patients (4%) in atrial fibrillation at 1-year postoperative assessment. All 7 patients in atrial fibrillation had ventricular rate b100 beats per minute, and only 1 of them had LV ejection fraction b50%. The multivariable predictors of early LVD were LVMI/LVEDD (HR 1.83, CI 1.59–1.98, P = 0.001), RWT N0.46 (HR 2.16, CI 1.21–4.99, P = 0.028); and older age (HR 1.62, CI 1.23–3.02, P = 0.024), Table 2. The presence of atrial fibrillation was not predictive of early LVD. Fig. 2 shows the LV ejection fraction of all 179 patients at 1 year post AVR. A decrease in ejection fraction N 10% occurred in 41 patients (23%). On multivariable analysis, the predictors of N10% decrease in ejection fraction were LVMI/LVEDD (HR 1.69, CI 1.23–2.08, P = 0.021) and RWT N 0.46 (HR 1.79, CI 1.11–3.54, P = 0.041). 3.3. Prevalence and predictors of late LVD
Fig. 1. Top panel: Preoperative cohort selection. There 856 patients with moderate-severe MAVD. The following patients were excluded: patients that met pre-defined exclusion criteria, follow-up b2 years, and patients with preoperative ejection fraction b50%. Bottom panel: Cohort selection from the time of aortic valve replacement, through evaluation at 1 year, and to evaluation at 5 years. There 39 patients excluded in the interval between evaluation at 1 year and 5 years. *Exclusion criteria described in the methods section; FU: follow-up, EF; ejection fraction; echo: echocardiogram.
A 5-year clinical and echocardiographic follow-up was complete in 140/179 (78%). There were 39/179 (31%) without a 5-year follow up for the following reasons: death (n = 21), loss of follow-up (n = 16) and no echocardiogram at 5 years (n = 2). Among the 140 patients with 5-year follow up data, 16 (13%) had an acute coronary syndrome or angiographic documentation of coronary artery disease after AVR. These patients were excluded in the analysis for predictors of late LVD. Late LVD was present 29/124 (23%) and 11 (9%) had an ejection fraction b 40%. Among the 29 patients with late LVD, 24 had early LVD and
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Table 1 Baseline clinical and echocardiographic data. Entire cohort (n = 179)
Normal LV function (n = 141)
Early LVD (n = 38)
P value
Male Age at AVR years Body surface area
134 (75%) 63 ± 8 2.0 ± 0.4
107 (76%) 62 ± 11 2.0 ± 0.4
27 (71%) 64 ± 9 2.0 ± 0.2
0.37 0.49 0.18
Echo data Aortic peak velocity, m/s Aortic mean gradient, mmHg Aortic valve area, cm2 Pressure half time, ms LV ejection fraction, % LVEDD, mm LVESD, mm LV posterior wall thickness, mm LV septal wall thickness, mm LVMI, g/m2 LVMI/LVEDD Relative wall thickness LV diastolic dysfunctiona LA volume index, ml/m2 RV systolic pressure, mm Hg Aortic dimension 46–50 mm Aortic dimension N50 mm
4.5 ± 0.4 47 ± 6 1.14 ± 0.30 296 ± 138 60 ± 4 61 ± 6 38 ± 3 13 ± 2 14 ± 3 181 ± 31 3.0 ± 0.1 0.44 ± 0.02 47 (26%) 34 ± 4 49 (41, 56) 36 (21%) 3 (3%)
4.4 ± 0.6 46 ± 12 1.13 ± 0.21 304 ± 128 60 ± 6 60 ± 4 38 ± 7 13 ± 3 14 ± 2 176 ± 35 2.9 ± 0.1 0.43 ± 0.04 21(22%) 33 ± 7 47(40, 56) 29 (21%) 2 (2%)
4.5 ± 0.7 48 ± 11 1.10 ± 0.19 291 ± 123 59 ± 5 61 ± 7 39 ± 4 14 ± 3 14 ± 2 190 ± 39 3.1 ± 0.2 0.46 ± 0.03 16 (42%) 36 ± 4 54 (50–59) 7 (18%)
0.41 0.39 0.64 0.18 0.09 0.18 0.27 0.19 0.66 0.033 0.008 0.001 0.004 0.037 0.036 0.41
Clinical Bicuspid/Unicuspid valve Rheumatic heart disease Aorta replacement Bioprosthetic valve Atrial fibrillation Diabetes Active smoking Creatinine clearance b60 ml/min Hypertension Hyperlipidemia
61 (34%) 21 (12%) 39 (22%) 77 (43%) 29 (16%) 21 (12%) 22 (12%) 17 (10%) 153(63%) 83(38%)
49 (35%) 16 (11%) 32 (22%) 60 (43%) 16 (11%) 17 (12%) 16 (11%) 13 (9%) 111(60%) 59(38%)
12 (32%) 5 (13%) 7 (18%) 17 (45%) 13 (34%) 4 (11%) 6 (16%) 4 (11%) 42(72%) 24(41%)
0.61 0.82 0.17 0.39 b0.0001 0.32 0.082 0.13 0.01 0.45
AVR: Aortic valve replacement. LA: Left atrium. LV: Left ventricle. LVEDD: Left ventricular end-diastolic dimension. LVESD: Left ventricular end-systolic dimension. LVMI: Left ventricular mass index. RV: Right ventricle. a LV diastolic dysfunction: Only 151 had diastolic assessment at baseline.
never recovered LV function while the other 5 had normal LV function at 1 year follow up but developed LVD afterwards. The clinical characteristics of these 5 patients with late onset LVD did not differ from the rest of the cohort. The multivariable predictors of late LVD were LVMI/LVEDD
N3.1 (HR 1.77, CI 1.24–2.01, P = 0.031) and RWT N0.46 (HR 1.65, CI 1.29–2.24, P = 0.014), Table 3. Fig. 2 shows the LV ejection fraction of all 124 patients at 5 years post AVR. Compared to the baseline ejection fraction prior to AVR, a decrease in ejection fraction N10% occurred in
Table 2 Predictors of Early LVD. Univariable
Age (per 10 year increase) Aortic peak velocity, m/s Pressure half time, ms LV ejection fraction N60% LVEDD, mm LVESD, mm LA volume index N35 ml/m2 LVMI (per 10 g/m3 increase) LVMI/LVEDD N3.1 Relative wall thickness N 0.46 Atrial fibrillationa Unicuspid/bicuspid valve Diabetes Hypertensionb Rheumatic heart disease
Multivariable
HR (95% CI)
P value
HR (95% CI)
P value
3.91 (2.61–4.21) 1.91 (2.61–4.21) 1.33 (0.86–2.32) 0.86 (0.46–1.19) 1.66 (0.26–4.17) 1.52 (0.71–2.19) 1.11 (0.33–2.81) 1.29 (1.08–1.78) 2.51 (1.02–3.12) 2.12 (1.53–3.94) 1.51 (0.63–2.44) 0.61(0.32–1.09) 1.55 (0.82–2.14) 1.38 (0.48–2.17) 1.05 (0.32–2.14)
0.001 0.007 0.42 0.092 0.31 0.39 0.44 0.012 0.016 0.007 0.26 0.081 0.093 0.091 0.24
1.62 (1.23–3.02) 2.12 (0.67–4.56)
0.024 0.16
1.34 (0.67–1.53) 1.83 (1.59–1.98) 2.16 (1.21–4.99)
0.37 0.001 0.028
HR: Hazard ratio. CI: Confidence interval. a Atrial fibrillation: documented atrial fibrillation within 6 months of clinic visit at 1-year post AVR. b Hypertension: systolic blood pressure N 140 mm Hg at clinic visit at 1-year post AVR.
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32 patients (26%). On multivariable analysis, the only predictor of N 10% decrease in ejection fraction at 5 years post AVR was RWT N0.46 (HR 1.85, CI 1.26–4.17, P = 0.034). The 16 patients with documented acute coronary syndrome were excluded from survival-free from LVD analysis. For the 164 patients included in the analysis, the prevalence of LVD was 16%, 21% and 23% at 1, 3 and 5 years respectively (Fig. 3).
3.4. Aortic valve prostheses There were 16 patients that had prosthetic valve dysfunction, and the presence of prosthetic dysfunction was not predictive of LVD. The mean gradient and effective orifice area at 1 year post AVR were 16 ± 3 mm Hg and 2.16 ± 0.25 cm2, while the mean gradient and effective orifice area at 5 years post AVR were 21 ± 4 mm Hg and 1.82 ± 0.41 cm2.
3.5. Death There were 21 deaths (10 cardiac, 9 non-cardiac, and 2 unknown) reported during the study period. The causes of death were congestive heart failure (n = 3); myocardial infarction (n = 2), endocarditis (n = 2), sudden death (n = 2), mechanical aortic prosthetic thrombosis (n = 1), stroke (n = 2), cancer (n = 4), sepsis (n = 1), renal failure (n = 2), and unknown cause (n = 2). For the patients that died, the median survival from the time of AVR was 2 years (IQR: 1–3). All-cause mortality was higher in patients with LVMI/LVEDD N 3.1 (P = 0.043) and RWT N 0.46 (P = 0.029, Fig. 4.
3.6. LV reverse remodeling An analysis of the trend in LVMI and RWT was performed for the 124 patients with 5-year follow-up and absence of coronary artery disease. The patients with late LVD had higher preoperative LVMI/LVEDD and RWT (3.1 ± 0.2 and 0.46 ± 0.03 vs 2.9 ± 0.1 and 0.43 ± 0.04, P b 0.008); at 1 year after AVR (3.1 ± 0.3 and 0.45 ± 0.03 vs 2.8 ± 0.2 and 0.41 ± 0.03, P b 0.003) and at 5 years after AVR (3.0 ± 0.2 and 0.44 ± 0.03 vs 2.7 ± 0.1 and 0.40 ± 0.02, P b 0.001). The patients with postoperative LVD also showed less regression of LV mass after AVR even after controlling for blood pressure, Fig. 4. 4. Discussion This is a retrospective review of 179 patients with moderate-severe MAVD to determine the prevalence and predictors of LVD after AVR. These are the main findings: 1) The prevalence of early and late LVD was 21% and 23% respectively, and the risk factors for LVD were older age and higher preoperative LV mass; 2) The patients with LVD has less LV reverse remodeling after AVR; 3) Higher preoperative LV mass was associated with all-cause mortality. 4.1. Prevalence of LVD This study reviewed the outcome of AVR in 179 patients with moderate-severe MAVD, normal LV function and no documented coronary artery disease. LVD was identified in 21% and 23% of the cohort at 1 and 5 years after AVR respectively. The current guideline recommendations for AVR are based on studies that showed excellent survival and preservation of LV function when AVR is performed prior to the onset of LVD in patients with isolated severe aortic stenosis or regurgitation [1–5,17–20] There are no guideline recommendations for the timing of AVR in MAVD, and as a result, a common practice is to apply the recommendations for the predominant lesion. The current study shows that LVD occurred in one-fifth of the patients with moderate-severe MAVD who underwent AVR, at the “appropriate time” based on the criteria for isolated aortic stenosis or regurgitation. This study identified older age and higher preoperative LV mass as risk factors for LVD. A large retrospective study of 4264 patients that underwent AVR for isolated or mixed lesions also showed that severe LV hypertrophy was the strongest predictor of LVD and death after AVR [21]. One-third of that cohort had MAVD and the severity of preoperative LV hypertrophy was higher in the MAVD subgroup compared to the patients with isolated aortic stenosis or regurgitation. It is important to note that coronary artery disease was present in 66% of that cohort making it difficult to determine if LVD was due to valvular heart disease or coronary artery disease. Additionally, one-quarter of that cohort had LVD prior to AVR. In contrast, the current study excluded patients with coronary artery disease and preoperative LVD thereby eliminating or at least minimizing these confounders. Notwithstanding, higher preoperative LV mass (LVMI/LVEDD N 3.1 and RWT N 0.46) was also identified as a predictor of LVD similar to the report by Beach and colleagues [21]. Several other studies have also reported an association between severe LV hypertrophy and cardiovascular adverse events in patients with isolated aortic stenosis [22–24]. 4.2. Combined pressure-volume load
Fig. 2. Bar chart showing the spectrum of LV ejection fraction a 1 year post AVR (top panel) and 5 years post AVR (bottom panel).
A major pitfall of determining the timing of AVR in MAVD based on the criteria for isolated lesion is the inherent assumption that the hemodynamic impact of combined pressure and volume load on the LV is not remarkably different from that of isolated pressure or volume load. Studies have shown that this assumption may not be correct [25,26]. Lamb and colleagues [25] showed that the ratio of LVMI/LV end diastolic volume decreased in patients with aortic stenosis but increased in
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Table 3 Predictors of Late LVD. Univariable
Age (per 10 year increase) Aortic peak velocity, m/s Prosthetic dysfunctiona Pressure half time, ms LV ejection fraction N60% LVEDD, mm LVESD, mm LA volume index N35 ml/m2 LVMI (per 10 g/m3 increase) LVMI/LVEDD N3.1 Relative wall thickness N0.46 Atrial fibrillationb Unicuspid/bicuspid valve Diabetes Hypertensionc Rheumatic heart disease a b c
Multivariable
HR (95% CI)
P value
2.27 (0.87–4.71) 1.55 (0.46–2.13) 1.23 (0.84–2.07) 2.12 (0.13–4.94) 1.33 (0.16–3.53) 3.81 (0.25–5.26) 1.29 (0.68–1.78) 2.53 (0.72–4.02) 1.51 (1.12–2.35) 1.94 (1.19–2.83) 2.55 (1.82–4.14) 3.25 (0.59–5.33) 1.01(0.62–2.13) 1.27 (0.87–1.71) 1.86 (1.14–2.15) 1.23 (0.14–3.07)
0.43 0.13 0.18 0.32 0.17 0.18 0.39 0.29 0.011 0.027 0.001 0.21 0.29 0.18 0.005 0.33
HR (95% CI)
P value
1.33 (0.42–1.84) 1.77 (1.24–2.01) 1.65 (1.29–2.24)
0.082 0.031 0.014
1.43 (0.55–2.14)
0.087
Prosthetic dysfunction: mean gradient N25 mm Hg or presence of ≥moderate regurgitation. Atrial fibrillation: documented atrial fibrillation within 6 months of clinic visit at 5-year post AVR. Hypertension: systolic blood pressure N140 mm Hg at clinic visit at 5-year post AVR.
patients with aortic regurgitation after AVR. AVR resulted in an improvement in diastolic function in the patients with aortic stenosis but worsening of diastolic function in the patients with aortic regurgitation in that series [25]. Similarly, another study comparing LV mass in 71 patients undergoing AVR showed that LVMI decreased in the patients with aortic stenosis but did not change significantly in the patients with aortic regurgitation [26]. These studies show that the LV response to pressure load and remodeling after AVR, differed from volume load and remodeling after AVR. It is therefore unrealistic to assume that the hemodynamic response of combined pressure and volume load will conform to the pattern of isolated pressure or volume load. Concentric LV hypertrophy is an adaptive mechanism characterized by parallel replication of new sarcomeres resulting in increased wall thickness and normalization of wall stress [27,28]. However severe LV hypertrophy can become “mal-adaptive” resulting in LV dysfunction and major adverse cardiovascular events [21–24,29]. Although, the exact mechanism resulting in adverse events is unclear, some data suggests that this may due to fibrosis resulting from a mismatch between myocardial blood supply and demand in the setting of severe LV hypertrophy [30]. There are emerging data about the use of T1 mapping technique in cardiac magnetic resonance imaging to quantify severity of fibrosis and perhaps improve risk stratification [30,31]. The goal of AVR is to prevent LVD and prolong life. All the patients in this study underwent AVR at the appropriate time based on the guideline
criteria for isolated aortic stenosis or regurgitation, and the yet some of these patients already had severe and mal-adaptive LV hypertrophy at the time of AVR. The cohort had normal preoperative LV ejection fraction, which is a load dependent index of LV contractility. Perhaps some of the patients already had decreased LV contractility prior to AVR, and this was masked by complex loading conditions present in MAVD. Are we operating too late? A different study design will be required to determine if mal-adaptive LV hypertrophy and subsequent LVD can be prevented by performing AVR earlier in patients with MAVD. Although the current study does not provide data about the optimal timing for AVR in this population, the authors showed that waiting until the occurrence of severe LV hypertrophy was associated with postoperative LVD and all-cause mortality. The patients with postoperative LVD showed less regression of LV mass after AVR even after controlling for blood pressure. 4.3. Limitations This study is based on a selected cohort of patients that survived for at least 2 years after AVR and the prevalence of LVD observed in this study may not be representative of all MAVD patients undergoing AVR. It is logical to anticipate that LVD may be more common than reported in this study because the patients that died perioperatively were excluded from this study. Although this study excluded the patients with coronary artery disease and also controlled for blood pressure and atrial fibrillation at the time of clinic visit, other confounders may have influenced the results because of the retrospective study design. The indications for AVR in these patients were symptoms and abnormal exercise test but the investigators were unable to accurately determine the time interval from onset of symptoms to AVR. Lastly, all-cause mortality in this study might be under-estimated because mortality data were abstracted from electronic medical records. However, this does not influence the finding that all-cause mortality was higher in patients with higher preoperative LV mass. 5. Conclusion
Fig. 3. Kaplan Meier curve showing the occurrence of LVD Out of the 179 patients enrolled in the study, only 163 patients without documented acute coronary syndrome were included in the analysis. LVD: left ventricular dysfunction, AVR: aortic valve replacement.
One-fifth of patients with moderate-severe MAVD and normal LV function develop LVD after AVR even in the absence of coronary artery disease. The severity of LV hypertrophy was associated with postoperative LVD and all-cause mortality. This study emphasizes the difference in the pathophysiology of MAVD compared to isolated aortic stenosis or regurgitation, and also highlights the paucity of evidence-based recommendation to guide
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Fig. 4. Top panel: Regression of left ventricular mass after aortic valve replacement (A) Comparison of regression of LVMI/LVEDD ratio between the patients with LVD (blue) and the patients without LVD (red). (B) Comparison of regression of RWT between the patients with LVD (blue) and the patients without LVD (red). Bottom panel: Comparison of the occurrence of LVD and all-cause mortality by preoperative left ventricular mass (A) Comparison of percentage of patients with early LVD (blue), late LVD (red) and death (green) between the patients with LVMI/LVEDD ratio ≤3.1 vs N3.1 (B) Comparison of percentage of patients with early LVD (blue), late LVD (red) and death (green) between patients with RWT ≤0.46 vs N0.46 LV: Left ventricle; LVD: Left ventricular dysfunction; LVMI: Left ventricular mass index; LVEDD: Left ventricular end diastolic dimension; RWT: Relative wall thickness.
management in this population. Perhaps LV mass should be considered in determining the timing of AVR, in addition to current criteria of symptoms and ejection fraction. A prospective study is required to validate these findings.
[7] [8]
Funding [9]
None. [10]
Conflict of interest None. [11]
Disclosures No relationships with industry. [12]
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