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Relation of Left Atrial Size, Cardiac Morphology, and Clinical Outcome in Asymptomatic Aortic Stenosis
Relation of Left Atrial Size, Cardiac Morphology, and Clinical Outcome in Asymptomatic Aortic Stenosis Nicolaj Lyhne Christensen, MD, PhDa,*, Jordi Sanchez Dahl, MD, PhDa, Rasmus Carter-Storch, MDa, Rine Bakkestrøm, MDa, Redi Pecini, MD, PhDa, Flemming Hald Steffensen, MD, PhDb, Eva Vad Søndergaard, MD, PhDa, Lars Melgaard Videbæk, MD, PhDa, and Jacob Eifer Møller, MD, PhD, DMSca Left atrial (LA) dilation in asymptomatic severe aortic stenosis (AS) may be an indicator of advanced disease. We aimed to investigate the association between LA volume index and left ventricular (LV) morphology assessed with cardiac magnetic resonance imaging (cMRI), and to assess the association with cardiac events. Ninety-two asymptomatic patients with aortic valve area <1 cm2, aortic peak jet velocity >3.5 m/s, and ejection fraction ≥50% were prospectively enrolled and divided according to echocardiographicderived LA volume index <35 ml/m2. Patients underwent echocardiography, cMRI, exercise testing, and were followed for the composite end point of death, readmission, or aortic valve replacement. Aortic valve area index was similar (0.45 ± 0.08 cm 2 /m 2 vs 0.45 ± 0.09 cm2/m2, p = 0.85) in patients with a dilated and normal LA. On cMRI patients with dilated LA were characterized by higher LV mass index (73 ± 17 g/m2 vs 66 ± 16 g/m2, p = 0.03), increased right ventricle (70 ± 14 ml/m2 vs 63 ± 12 ml/m2, p = 0.01) and LV enddiastolic volume index (84 ± 18 ml/m2 vs 77 ± 16 ml/m2, p = 0.05), and higher brain natriuretic peptide. Late enhancement pattern was similar. During follow-up 20 events were recorded in patients with LA dilation compared with 8 in patients with normal LA (adjusted hazard ratio 2.77, 95% confidence interval 1.19 to 6.46, p = 0.02); also B-type natriuretic peptide >125 pg/ml was associated with adverse outcome (adjusted hazard ratio 3.63, 95% confidence interval interval 1.28 to 10.32, p = 0.02). LA dilation is associated with LV remodeling and provides prognostic information in severe asymptomatic AS. © 2017 Elsevier Inc. All rights reserved. (Am J Cardiol 2017;120:1877–1883) Aortic stenosis (AS) is characterized by excessive pressure load on the left ventricle (LV). Classically, longstanding pressure overload will cause LV hypertrophy, myocardial fibrosis, increased chamber stiffness, impaired relaxation, and increased myocardial oxygen demand.1,2 In response to myocardial stretching, B-type natriuretic peptide (BNP) is secreted by the ventricles and reduces systemic vascular resistance and central venous pressure. The left atrium (LA), a thin-walled cardiac chamber prone to dilation when left-sided intracavitary pressures increase, is a robust marker reflecting long-term duration and severity of increased LA pressure.3,4 When LV compensatory mechanisms fail, symptoms will develop and surgery is indicated.5 The transition from an asymptomatic to symptomatic state is often difficult to determine and detection of LA dilation in asymptomatic a Department of Cardiology, Odense University Hospital, 5000 C Odense, Denmark; and bLillebaelt Hospital, 7100 Vejle, Denmark. Manuscript received April 26, 2017; revised manuscript received and accepted July 20, 2017. Funding sources: The Danish Heart Association, Copenhagen (13-04R94-A4564-22805); Odense University Hospital Free Research Fund, Odense. Region of Southern Denmark Research Funds, Region of Southern Denmark; University of Southern Denmark, Odense. A and E Danielsens Foundation, Copenhagen. Dir. Bønnelycke Foundation, Copenhagen. See page 1882 for disclosure information. *Corresponding author: Tel: 4531792065; fax: 4563110497. E-mail address: [email protected] (N.L. Christensen).
0002-9149/$ - see front matter © 2017 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.amjcard.2017.07.101
patients may be a morphologic sign of imminent transition. We hypothesize that LA dilation is a morphologic sign associated with LV remodeling and increased risk of progression to a symptomatic state in patients with severe asymptomatic AS. The association between echocardiographically determined LA volume index (LAVi) and LV morphology was assessed on cMRI and exercise capacity, and the association of LA dilation with risk of referral to aortic valve replacement, unplanned readmission, and death in patients with asymptomatic severe AS was investigated. Methods A total of 100 patients aged ≥18 years with severe asymptomatic AS (aortic valve area (AVA) <1 cm2 and maximal aortic peak velocity >3.5 m/s) and LV ejection fraction (LVEF) >50% were prospectively enrolled. Patients with chronic kidney disease (p-creatinine ≥200 µmol/L), permanent ventricular pacing, chronic atrial fibrillation, inability to perform exercise testing, and co-existent more than mild mitral valve disease or aortic insufficiency were excluded. Further, 8 patients (8%) were excluded from cMRi analysis due to claustrophobia, leaving 92 patients for further study. Patients had been judged asymptomatic by an experienced cardiologist not taking part in the study before enrollment and reconfirmed by the study staff at the time of inclusion. The study was registered at the Danish Data Protection Agency and ClinicalTrials.gov (NCT02395107) and approved by the local ethics www.ajconline.org
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committee (S-20130067), and all patients signed an informed consent form before enrollment. A transthoracic echocardiogram was performed on a Vivid E9 (General Electric, Horten, Norway) and stored for later blinded analysis. Frame rate was kept at minimum 60/s. Aortic valve anatomy and flow was assessed in multiple apical views to obtain maximal flow velocity across the valve. Pulse wave Doppler flow velocity was recorded with a sample volume placed in the LV outflow tract (LVOT). LVOT diameter was measured 5 mm adjacent to the aortic valve. AVA was calculated using the continuity equation. Velocity measurements were transformed to gradients by the simplified Bernoulli equation. Mitral inflow pattern was assessed with the pulsed wave Doppler sample volume at the mitral leaflet tips and basal myocardial velocity profile recorded with pulsed wave tissue-Doppler at the medial mitral annulus. Diastolic function was classified according to guidelines.6 LV volumetric measurements and LVEF were calculated from 4- and 2-chamber using the biplane Simpson’s method. Maximal LA volume was determined before mitral valve opening and LA minimum volume before mitral valve closure. Patients were divided into 2 groups according to an echocardiographicderived normal LAVi (<35 ml/m2) and dilated LA (≥35 ml/m2).7 LA function was assessed using 2-dimensional speckle tracking analysis in the apical 4- 3-, and 2-chamber views of the LA. The semi-automated algorithm was used for drawing the region of interest between LA endocardial and epicardial borders, with manual adjustment to cover the exact thickness of the LA wall. From the average of a total of 18 segmental strain curves, global peak atrial longitudinal strain (PALS) was derived as the maximum positive strain value during systole. cMRI was performed on a Philips Ingenia 1.5T scanner with Omega HP gradient system (Philips Electronics, Koninklijke, The Netherlands). Sequential short-axis slices enclosing the entire heart were obtained during multiple breath hold sequences acquiring slices of 8-mm thickness. Delayed enhancement imaging was performed 10 to 15 minutes after administration of 0.1 mmol/kg gadoterate meglumine (Dotarem, Guerbet, Aulnay-Bois, France). Optimal inversion time (TI), to null the myocardium, was determined using a Look-Locker sequence with multiple images with varying TI. Images were analyzed blinded for clinical and echocardiographic data by an experienced examiner using Philips Intellispace software package (2.6.3.5, 2013). Ventricular chamber volumes were measured from short axis slices and LV mass was estimated by multiplying mass volume (difference in epicardial- and endocardial cross-sectional area times the sum of slice thickness gap), derived in end-diastole, by myocardial density (1.05g/ml).8 Papillary muscles were considered as part of the LV cavity and excluded from LV mass.9 Phase velocity flow mapping of flow volumes in the aorta and pulmonary trunk were used to assess stroke volume. Late enhancement pattern was reported as midwall, ischemic, and “nonspecific.” Radial and longitudinal distribution as well as segment thickness was recorded and counted using the 17segment cardiac model.10 A cycle ergometer stress test was performed on a Cardiosys system—software version 4.1 (General Electric, Freiburg, Germany). A test protocol with increments of 25 W increases every 2 minutes until exhaustion was used. Maximal
oxygen consumption rate per kilogram (VO2max) was estimated from maximal achieved watts11 and converted to metabolic equivalents. Expected VO2max was calculated from the Wasserman-Hansen equations.12 Blood was drawn from an antecubital vein after at least 10 minutes of rest. Samples were collected in ethylenediamineteraacetic acid (EDTA) tubes and stored at −80°C for later analysis of brain natriuretic peptide (BNP) using a BNP immunoassay (Abbott, Wiesbaden, Germany). A composite end point of unplanned hospital admissions (for atrial fibrillation, heart failure, or acute coronary syndrome), aortic valve replacement, and death was recorded. Decision of aortic valve replacement was done by a heartteam not participating in the study according to current guidelines.13 Follow-up for composite end point was done by review of electronic hospital records and using the Danish Civil Registration System where all deaths in Denmark are registered within 2 weeks. Follow-up was completed in August 2016. Unless otherwise stated, data are mean ± standard deviation or median (interquartile range [IQR]). Differences in normally distributed continuous variables between groups were tested using analysis of variance (ANOVA) and Wilcoxon rank-sum test was used for variables with skewed distribution. Categorical variables were tested for association with the chi-square test. Biomarker measurements were log-transformed due to a skewed distribution. Kaplan-Meier time to event models were used to generate cumulative survival curves for composite end point and groups were compared with the log-rank test. Univariable and multivariable Cox analysis adjusting for age, gender, and aortic mean gradient was used for to assess potential predictors. The proportional hazard model was validated by log-log plots to assess proportionality, and Martingale residuals were calculated and graphed, adding a smoother for assumption of linearity. A value of p <0.05 on a 2-tailed test was considered statistically significant. All tests were performed on STATA/SE statistical package 14.1 (StataCorp LP, Texas). Results Clinical data for the 92 patients enrolled is shown in Table 1. Forty-five patients (49%) had LA dilation measured by echocardiography. A diagnosis of hypertension was more frequent in the group with a dilated LA, otherwise clinical data was similar in the 2 groups. Mean arterial blood pressure was equal between LAVi groups (93 ± 10 mmHg vs 94 ± 10 mmHg, p = 0.63). BNP was higher in patients with LA dilation (60 (32 to 114) vs 43 (27 to 75), p = 0.04). Doppler-derived AVA was similar in patients with a normal and dilated LAVi (0.83 ± 0.14 vs 0.83 ± 0.17 cm2, p = 0.97; Table 2). Further, no differences in Doppler-derived peak aortic transvalvular velocity or mean gradient were found (Figure 1). Seventeen patients (81%) with LA dilation had diastolic function grade ≥2 compared with 27 (39%) patients with a normal LA (p = 0.004). Peak mitral inflow velocity (E) was higher in patients with LA dilation and E/e′ was increased (14 ± 4 vs 12 ± 5, p = 0.05; Table 2). On cMRI, patients with dilated LA had higher LV mass index (73 ± 17 vs 66 ± 16 g/m2, p = 0.03). Patients with dilated LA had increased RV volume index (70 ± 14 vs 63 ± 12 ml/m2,
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Table 1 Demographic data Left atrial volume index (ml/m2) Variable Age (years) Men Body surface area (m2) Coronary heart disease Hypertension Peripheral artery disease Diabetes mellitus Diuretic therapy Beta-blocker therapy Calcium channel blocker therapy Angiotensin inhibitor therapy Statin therapy E-GFR (ml/min)
All patients (N = 92)
<35 ml/m2 (N = 47)
≥ 35 ml/m2 (N = 45)
p-Value
74 ± 8 52 (57%) 1.86 ± 0.20 3 (3%) 63 (68%) 1 (1%) 12 (13%) 29 (32%) 13 (14%) 26 (28%) 41 (45%) 43 (47%) 75 ± 17
73 ± 7 24 (51%) 1.85 ± 0.19 1 (2%) 26 (55%) 1 (2%) 4 (9%) 16 (34%) 5 (11%) 5 (11%) 16 (34%) 21 (45%) 74 ± 15
75 ± 9 28 (62%) 1.86 ± 0.22 2 (4%) 37 (82%) 0 (0%) 8 (18%) 13 (29%) 8 (18%) 21 (47%) 25 (56%) 22 (49%) 76 ± 18
0.21 0.30 0.93 0.61 0.01 1.0 0.23 0.66 0.38 <0.001 0.06 0.84 0.63
Data are number and (%) or mean ± standard deviation. E-GFR = estimated glomerular filtration rate.
Table 2 Echocardiographic and exercise parameters according to Left atrial volume index Left atrial volume index (ml/m2) Variable ECHOCARDIOGRAPHY Left atrial volume index (ml/m2) Relative wall thickness Left ventricular mass (g) Left ventricular mass index (g/m2) Aortic valve area (cm2) Aortic valve area index (cm2/m2) Aortic valve Vmax (m/s) Aortic valve mean gradient (mmHg) E velocity (m/s) A velocity (m/s) EA-ratio Deceleration time (msec) E/e’ medial Diastolic function Peak atrial longitudinal strain (%) TAPSE (mm) S’ right ventricle (cm/s) Brain natriuretic peptide (pg/ml) EXERCISE TEST Maximal workload (Watts) % Expected VO2max Maximal workload (METS) Maximal heart rate (bpm) % Expected heart rate Maximum systolic blood pressure (mmHg)
All patients (N = 92)
<35 ml/m2 (N = 47)
≥ 35 ml/m2 (N = 45)
p-Value
36 ± 8 0.47 ± 0.08 186 ± 39 100 ± 19 0.83 ± 0.15 0.45 ± 0.08 4.20 ± 0.57 45 ± 14 0.77 ± 0.22 1.03 ± 0.30 0.78 ± 0.24 294 ± 93 13 ± 5 22/49/21/0 26 ± 6 24 ± 3 13 ± 2 51 (29–70)
29 ± 5 0.47 ± 0.07 181 ± 38 98 ± 20 0.83 ± 0.14 0.45 ± 0.08 4.11 ± 0.47 42 ± 11 0.72 ± 0.22 0.99 ± 0.28 0.75 ± 0.23 295 ± 88 12 ± 5 13/30/4/0 26 ± 5 25 ± 4 13 ± 3 43 (27–75)
43 ± 5 0.48 ± 0.08 191 ± 39 103 ± 19 0.83 ± 0.17 0.45 ± 0.09 4.30 ± 0.65 47 ± 17 0.83 ± 0.21 1.08 ± 0.31 0.81 ± 0.26 294 ± 100 14 ± 4 9/19/17/0 26 ± 7 24 ± 3 14 ± 2 60 (32–114)
0.32 0.21 0.20 0.97 0.85 0.13 0.10 0.02 0.17 0.24 0.95 0.05 0.004 0.68 0.13 0.77 0.04
115 ± 33 117 ± 23 6±2 138 ± 19 94 ± 12 177 ± 16
113 ± 31 114 ± 21 6±2 143 ± 18 97 ± 12 179 ± 15
118 ± 34 121 ± 25 6±2 133 ± 19 92 ± 12 175 ± 18
0.50 0.17 0.50 0.02 0.05 0.28
Data are number and (%) or mean ± standard deviation. TAPSE = tricuspid annular plane systolic excursion.
p = 0.01) and LV end-diastolic volume index (84 ± 18 vs 77 ± 16 ml/m2, p = 0.05) and larger right atrial volume index (52 ± 12 vs 47 ± 11 ml/m2, p = 0.03; Table 3 and Figure 1). Late gadolinium enhancement (LGE) was performed in 78 patients where 15 patients had midwall fibrosis, 3 had isch-
emic fibrosis, and 3 had nonspecific fibrosis. Overall, no difference in presence of fibrosis between LAVi groups was found (p = 0.53; Table 3). Estimated maximal oxygen peak consumption did not differ between patients with a normal and dilated LA (Table 2). Only 5 patients achieved lower than
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Figure 1. RV and LV size and LV mass and aortic mean gradient according to left atrium volume index. (A) Upper panel left—LV end-diastolic volume index between LAVi groups. (B) Upper panel right—RV end-diastolic volume index between LAVi groups. (C) Lower panel left—LV mass index between LAVi groups during peak exercise. (D) Lower panel right—Aortic mean gradient between LAVi groups. p Value: log-rank test.
Table 3 Magnetic resonance morphology according to echocardiographic-derived left atrial volume Index Left atrial volume index (ml/m2) Variable Magnetic Resonance Left ventricular end-diastolic volume index (ml/m2) Left ventricular end-systolic volume index (ml/m2) Left ventricular ejection fraction (%) Right atrial volume index (ml/m2) Right atrial emptying fraction (%) Right ventricular end-diastolic volume index (ml/m2) Right ventricular end-systolic volume index (ml/m2) Right ventricular ejection fraction (%) Left ventricular mass (g) Left ventricular mass index (g/m2) Aortic stroke volume (ml) Aortic stroke volume index (ml/m2) Aortic regurgitant fraction (%) Fibrosis* Data are number and (%) or mean ± standard deviation. * 78 patients were eligible for analysis of fibrosis.
All patients (N = 92)
< 35 ml/m2 (N = 47)
≥ 35 ml/m2 (N = 45)
p-Value
80 ± 17 31 ± 10 62 ± 7 50 ± 12 42 ± 9 66 ± 14 26 ± 7 62 ± 7 130 ± 36 69 ± 17 70 ± 18 38 ± 8 8±6 21 (27%)
77 ± 16 30 ± 10 61 ± 7 47 ± 11 43 ± 10 63 ± 12 24 ± 7 61 ± 7 122 ± 35 66 ± 16 69 ± 19 37 ± 9 7±7 9 (24%)
84 ± 18 32 ± 11 62 ± 7 52 ± 12 41 ± 9 70 ± 14 27 ± 8 62 ± 6 137 ± 37 73 ± 17 71 ± 18 38 ± 8 9±6 12 (30%)
0.05 0.44 0.37 0.03 0.48 0.01 0.15 0.51 0.05 0.03 0.66 0.68 0.15 0.53
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Table 4 Univariate and multivariate analysis of cardiac magnetic resonance parameters and echocardiographic parameters. Predictors of composite end point of death, unplanned hospitalization and aortic valve replacement Variable Cardiac Magnetic resonance Left ventricular end-diastolic volume index (ml/m2) Left ventricular end-systolic volume index (ml/ m2) Left ventricular mass index (ml/m2) Left ventricular ejection fraction (%) Right ventricular end-diastolic volume index (ml/m2) Right atrial volume index (ml/m2) Overall fibrosis Echocardiography Left atrial volume index (ml/m2) Left atrial volume index > 35 ml/m2 Aortic mean gradient (mmHg) Aortic peak velocity (m/s) Aortic valve Vmax > 4.5 m/s Aortic valve area (cm2) Brain natriuretic peptide > 125 pg/ml
HR (95% CI)
p-Value
HR (95% CI)*
p-Value
1.04 (1.02–1.06) 1.05 (1.02–1.08) 1.03 (1.01–1.05) 0.97 (0.93–1.02) 1.03 (1.01–1.06) 1.03 (1.00–1.06) 0.79 (0.32–1.94)
<0.001 0.003 0.002 0.27 0.005 0.04 0.60
1.03 (1.01–1.06) 1.04 (1.00-1-07) 1.02 (0.99–1.05) 0.97 (0.92–1.02) 1.03 (0.99–1.05 1.02 (0.99–1.05) 1.17 (0.44–3.11)
0.006 0.03 0.14 0.28 0.06 0.17 0.76
1.09 (1.04–1.14) 2.93 (1.28–6.68) 1.02 (1.00-1-04) 1.86 (1.10–3.15) 2.75 (1.26–6.01) 1.05 (0.32–3.47) 3.24 (1.35–7.77)
0.001 0.01 0.02 0.02 0.01 0.93 0.008
1.07 (1.02–1.12) 2.77 (1.19–6.46) 1.03 (1.01–1.05) † 2.17 (1.21–3.87) † 3.19 (1.44–7.06) † 0.82 (0.21–3.30) † 3.63 (1.28–10.32)
0.008 0.02 0.007 0.009 0.004 0.79 0.02
Data are number and (%) or mean ± standard deviation. * Adjusted for age, sex and aortic mean gradient. † Adjusted for age and sex only.
90% of expected estimated oxygen consumption. There was no correlation between LAVi and maximal exercise capacity (watts) but PALS correlated with maximal workload (r = 0.30, p = 0.03). During median follow-up time of 358 days, 28 events were recorded. Twenty-two patients developed symptoms and were referred for AVR, there were 4 deaths (1 sudden cardiac death) and 2 unplanned hospitalizations (1 myocardial infarction and 1 atrial fibrillation). In patients with LAVi ≥35 ml/m2, 20 patients experienced the composite end point (n = 14 AVR, n = 1 atrial fibrillation, n = 1 acute myocardial infarction) compared with 8 patients (n = 8, AVR) with normal LAVi, p = 0.008 (Figure 2 and Table 4). Apart from LAVi, BNP >125 pg/ml and LV volumes on cMRI were predictive of the composite end point, whereas LV mass index only in univariate analysis was predictive (Table 4). Discussion The present study demonstrates, in patients with severe asymptomatic AS, that LA volume assessed on conventional echocardiography is associated with more advanced LV remodeling and adverse outcome but apparently unrelated to focal myocardial fibrosis and reduced exercise capacity. AVR should be considered in asymptomatic patients with very severe AS (peak aortic jet velocity ≥5m/s), rapidly progressing disease, reduced LV ejection fraction <50%, or pathologic stress test. AS is a slowly progressive disease where myocardial hypertrophy with increased wall thickness counterbalances the increase in LV end-systolic pressure, maintaining peak systolic wall stress, and preserving an adequate stroke volume. However, the preservation of a normal cardiac output will occur at the expense of elevated LV filling pressures secondary to increased LV myocardial stiffness and diastolic dysfunction. As the LA is directly exposed to LV pressures through the open mitral valve during diastole, LA
Figure 2. Kaplan-Meier time to event analysis of predictor variables for the composite end point of unplanned hospitalization, death, and aortic valve replacement. (A) Event-free survival for the composite end point according to LAVi (35 ml/m2). (B) Event-free survival for the composite end point according to BNP >125 pg/ml. p Value: log-rank test.
size is therefore largely determined by the same factors that influence diastolic function.14 The present study demonstrates that LA dilation is frequently observed in asymptomatic patients with severe AS and associated with advanced
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diastolic dysfunction, thus supporting more advanced disease in patients with LA dilation.15,16 Although we did find an association between LV mass on cMRI and LA volume, this was relatively weak, and despite severe AS, only 29% of the population had LV hypertrophy on cMRI. In contrast a considerably stronger association was found with LV enddiastolic volume index. From a physiologic standpoint, preload can be defined as the initial stretching of cardio myocytes before contraction and is therefore closely associated with LV end diastolic volume. Thus the association between LA dilation and LV end-diastolic volume could be conceptualized to support the association between LA volume and preload. The transition from the asymptomatic state with adaptive LV hypertrophy to heart failure in AS has been suggested importantly related to development of myocardial fibrosis. Histologically and using LGE technique, fibrosis has been shown as a useful postoperative predictor for clinical outcome following AVR in symptomatic patients.17–19 However, midwall replacement fibrosis likely represents a late manifestation of the remodeling process during the course of AS.20 This could possibly explain that we only detected focal fibrosis in less than 1/3 and classic midwall fibrosis in even less. Studies have further suggested diffuse fibrosis quantitatively assessed by T1-mapping to be present even in moderate AS where it was found to be associated with LA size.21 The event rate in the present study was high but comparable with other reports.22 Data suggested that LAVi was a predictor of the composite end point in a population with severe AS. This is in agreement with other small-cohort studies of patients with severe AS, demonstrating that LA size is associated with the development of symptoms in asymptomatic patients23 and that LA size is increased among symptomatic patients.24 These findings are, however, somewhat in contrast to data from the SEAS study where LA dilation was not identified as a prognostic marker in patients with mild to moderate AS. This may reflect that, in severe AS, LAVi is a marker of changes in LV remodeling yet to occur in mild to moderate AS, and possibly other causes of LA dilation may be prevalent in the SEAS population unrelated to AS such as hypertension that would not be expected to be predictive of AVR.25 Thus, although LA size was increased, intrinsic atrial function seems relatively preserved, possibly through same mechanisms counterbalancing LV pressure overload (atrial hypertrophy). Interestingly, we were not able to demonstrate that LA function (PALS) was associated with our combined end point. In a small series of patients with AS, O’Connor and colleagues demonstrated that LA volume did not reflect the presence of intrinsic LA dysfunction, but also noted that LA emptying fraction was not different than healthy control patients.26 These findings would suggest that filling pressures seem more important than LA function in the development of symptoms in patients with severe AS. In asymptomatic AS Bergler-Klein et al. have showed that patients with a baseline BNP > 130 pg/ml were more likely to develop symptoms during follow-up,27 which is supported by this study showing a reduced event-free survival when BNP exceeds 125 pg/ml. Further, BNP was higher in patients with LA dilation. Identification of truly asymptomatic patients is difficult and some mildly symptomatic patients may have been included in the present study. However, with strenuous exercise we found maximal work capacity and estimated VO2max
achieved was normal or better in the vast majority and unrelated to LA dilation. Thus, indicating that patients were true asymptomatic with well-adapted compensatory mechanisms. Despite a high event rate the overall number of events was relatively low with a potential risk of overfitting the prognostic models. Thus, survival analyses may be associated with uncertainty. Despite this, LAVi was predictive of the composite end point, but larger prospective studies are needed before a general recommendation to use LA volume in risk stratification of patients with asymptomatic AS can be recommended. In studies of predictors of AVR the un-blinded nature of most studies are pivotal when interpreting the data due to risk of “confounding by severity.” However, heart team deciding on referral for surgery was blinded for all cMRI data and the measured LA volume index performed as part of this study. T1 mapping was not done as part of the cMRI protocol, and we can only speculate how diffuse fibrosis would have related to LA size. The present study demonstrates that LV remodeling is associated to LA size in severe asymptomatic AS. Further LAVi was despite being unrelated to exercise capacity and myocardial fibrosis, predictive of the composite end point. Morphological parameters should be emphasized as subclinical early warnings and assessed with other functional parameters during follow-up. Disclosure The authors have no conflicts of interest to disclose. 1. Ozkan A, Kapadia S, Tuzcu M, Marwick TH. Assessment of left ventricular function in aortic stenosis. Nat Rev Cardiol 2011;8:494–501. 2. Elmariah S. Patterns of left ventricular remodeling in aortic stenosis: therapeutic implications. Curr Treat Options Cardiovasc Med 2015;17:391. 3. Simek CL, Feldman MD, Haber HL, Wu CC, Jayaweera AR, Kaul S. Relationship between left ventricular wall thickness and left atrial size: comparison with other measures of diastolic function. J Am Soc Echocardiogr 1995;8:37–47. 4. Appleton CP, Galloway JM, Gonzalez MS, Gaballa M, Basnight MA. Estimation of left ventricular filling pressures using two-dimensional and Doppler echocardiography in adult patients with cardiac disease. Additional value of analyzing left atrial size, left atrial ejection fraction and the difference in duration of pulmonary venous and mitral flow velocity at atrial contraction. J Am Coll Cardiol 1993;22:1972–1982. 5. Nishimura RA, Otto CM, Bonow RO, Carabello BA, Erwin JP 3rd, Guyton RA, O’Gara PT, Ruiz CE, Skubas NJ, Sorajja P, Sundt TM 3rd, Thomas JD, Anderson JL, Halperin JL, Albert NM, Bozkurt B, Brindis RG, Creager MA, Curtis LH, DeMets D, Guyton RA, Hochman JS, Kovacs RJ, Ohman EM, Pressler SJ, Sellke FW, Shen WK, Stevenson WG, Yancy CW. 2014 AHA/ACC guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Thorac Cardiovasc Surg 2014;148:e1–e132. 6. Nagueh SF, Smiseth OA, Appleton CP, Byrd BF 3rd, Dokainish H, Edvardsen T, Flachskampf FA, Gillebert TC, Klein AL, Lancellotti P, Marino P, Oh JK, Popescu BA, Waggoner AD. Recommendations for the evaluation of left ventricular diastolic function by echocardiography: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr 2016;29:277–314. 7. Lang RM, Badano LP, Mor-Avi V, Afilalo J, Armstrong A, Ernande L, Flachskampf FA, Foster E, Goldstein SA, Kuznetsova T, Lancellotti P, Muraru D, Picard MH, Rietzschel ER, Rudski L, Spencer KT, Tsang W, Voigt JU. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Eur Heart J Cardiovasc Imaging 2015;16:233–270.
Valvular Heart Disease/Left Atrial Dilation in Aortic Stenosis 8. Schulz-Menger J, Bluemke DA, Bremerich J, Flamm SD, Fogel MA, Friedrich MG, Kim RJ, von Knobelsdorff-Brenkenhoff F, Kramer CM, Pennell DJ, Plein S, Nagel E. Standardized image interpretation and post processing in cardiovascular magnetic resonance: Society for Cardiovascular Magnetic Resonance (SCMR) board of trustees task force on standardized post processing. J Cardiovasc Magn Reson 2013;15:35. 9. Kawel-Boehm N, Maceira A, Valsangiacomo-Buechel ER, VogelClaussen J, Turkbey EB, Williams R, Plein S, Tee M, Eng J, Bluemke DA. Normal values for cardiovascular magnetic resonance in adults and children. J Cardiovasc Magn Reson 2015;17:29. 10. Cerqueira MD, Weissman NJ, Dilsizian V, Jacobs AK, Kaul S, Laskey WK, Pennell DJ, Rumberger JA, Ryan T, Verani MS. Standardized myocardial segmentation and nomenclature for tomographic imaging of the heart. A statement for healthcare professionals from the Cardiac Imaging Committee of the Council on Clinical Cardiology of the American Heart Association. Int J Cardiovasc Imaging 2002;18:539–542. 11. Astrand PO. Quantification of exercise capability and evaluation of physical capacity in man. Prog Cardiovasc Dis 1976;19:51–67. 12. Guazzi M, Adams V, Conraads V, Halle M, Mezzani A, Vanhees L, Arena R, Fletcher GF, Forman DE, Kitzman DW, Lavie CJ, Myers J. EACPR/AHA Scientific Statement. Clinical recommendations for cardiopulmonary exercise testing data assessment in specific patient populations. Circulation 2012;126:2261–2274. 13. Vahanian A, Alfieri O, Andreotti F, Antunes MJ, Baron-Esquivias G, Baumgartner H, Borger MA, Carrel TP, De Bonis M, Evangelista A, Falk V, Iung B, Lancellotti P, Pierard L, Price S, Schafers HJ, Schuler G, Stepinska J, Swedberg K, Takkenberg J, Von Oppell UO, Windecker S, Zamorano JL, Zembala M. Guidelines on the management of valvular heart disease (version 2012). Eur Heart J 2012;33:2451–2496. 14. Matsuda M, Matsuda Y. Mechanism of left atrial enlargement related to ventricular diastolic impairment in hypertension. Clin Cardiol 1996;19:954–959. 15. Pritchett AM, Mahoney DW, Jacobsen SJ, Rodeheffer RJ, Karon BL, Redfield MM. Diastolic dysfunction and left atrial volume: a populationbased study. J Am Coll Cardiol 2005;45:87–92. 16. Aljaroudi W, Alraies MC, Halley C, Rodriguez L, Grimm RA, Thomas JD, Jaber WA. Impact of progression of diastolic dysfunction on mortality in patients with normal ejection fraction. Circulation 2012;125:782– 788. 17. Milano AD, Faggian G, Dodonov M, Golia G, Tomezzoli A, Bortolotti U, Mazzucco A. Prognostic value of myocardial fibrosis in patients with
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severe aortic valve stenosis. J Thorac Cardiovasc Surg 2012;144:830– 837. Azevedo CF, Nigri M, Higuchi ML, Pomerantzeff PM, Spina GS, Sampaio RO, Tarasoutchi F, Grinberg M, Rochitte CE. Prognostic significance of myocardial fibrosis quantification by histopathology and magnetic resonance imaging in patients with severe aortic valve disease. J Am Coll Cardiol 2010;56:278–287. Weidemann F, Herrmann S, Stork S, Niemann M, Frantz S, Lange V, Beer M, Gattenlohner S, Voelker W, Ertl G, Strotmann JM. Impact of myocardial fibrosis in patients with symptomatic severe aortic stenosis. Circulation 2009;120:577–584. Mewton N, Liu CY, Croisille P, Bluemke D, Lima JA. Assessment of myocardial fibrosis with cardiovascular magnetic resonance. J Am Coll Cardiol 2011;57:891–903. Lee SP, Lee W, Lee JM, Park EA, Kim HK, Kim YJ, Sohn DW. Assessment of diffuse myocardial fibrosis by using MR imaging in asymptomatic patients with aortic stenosis. Radiology 2015;274:359– 369. Pellikka PA, Sarano ME, Nishimura RA, Malouf JF, Bailey KR, Scott CG, Barnes ME, Tajik AJ. Outcome of 622 adults with asymptomatic, hemodynamically significant aortic stenosis during prolonged followup. Circulation 2005;111:3290–3295. Lancellotti P, Donal E, Magne J, Moonen M, O’Connor K, Daubert JC, Pierard LA. Risk stratification in asymptomatic moderate to severe aortic stenosis: the importance of the valvular, arterial and ventricular interplay. Heart 2010;96:1364–1371. Dahl JS, Christensen NL, Videbaek L, Poulsen MK, Carter-Storch R, Hey TM, Pellikka PA, Steffensen FH, Moller JE. Left ventricular diastolic function is associated with symptom status in severe aortic valve stenosis. Circ Cardiovasc Imaging 2014;7:142–148. Dalsgaard M, Egstrup K, Wachtell K, Cramariuc D, Kjaergaard J, Gerdts E, Hassager C. Left atrial volume as predictor of valve replacement and cardiovascular events in patients with asymptomatic mild to moderate aortic stenosis. Echocardiography 2013;30:1008–1014. O’Connor K, Magne J, Rosca M, Pierard LA, Lancellotti P. Left atrial function and remodelling in aortic stenosis. Eur J Echocardiogr 2011;12:299–305. Bergler-Klein J, Klaar U, Heger M, Rosenhek R, Mundigler G, Gabriel H, Binder T, Pacher R, Maurer G, Baumgartner H. Natriuretic peptides predict symptom-free survival and postoperative outcome in severe aortic stenosis. Circulation 2004;109:2302–2308.
0002-9149/$ - see front matter © 2017 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.amjcard.2017.07.101
patients may be a morphologic sign of imminent transition. We hypothesize that LA dilation is a morphologic sign associated with LV remodeling and increased risk of progression to a symptomatic state in patients with severe asymptomatic AS. The association between echocardiographically determined LA volume index (LAVi) and LV morphology was assessed on cMRI and exercise capacity, and the association of LA dilation with risk of referral to aortic valve replacement, unplanned readmission, and death in patients with asymptomatic severe AS was investigated. Methods A total of 100 patients aged ≥18 years with severe asymptomatic AS (aortic valve area (AVA) <1 cm2 and maximal aortic peak velocity >3.5 m/s) and LV ejection fraction (LVEF) >50% were prospectively enrolled. Patients with chronic kidney disease (p-creatinine ≥200 µmol/L), permanent ventricular pacing, chronic atrial fibrillation, inability to perform exercise testing, and co-existent more than mild mitral valve disease or aortic insufficiency were excluded. Further, 8 patients (8%) were excluded from cMRi analysis due to claustrophobia, leaving 92 patients for further study. Patients had been judged asymptomatic by an experienced cardiologist not taking part in the study before enrollment and reconfirmed by the study staff at the time of inclusion. The study was registered at the Danish Data Protection Agency and ClinicalTrials.gov (NCT02395107) and approved by the local ethics www.ajconline.org
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committee (S-20130067), and all patients signed an informed consent form before enrollment. A transthoracic echocardiogram was performed on a Vivid E9 (General Electric, Horten, Norway) and stored for later blinded analysis. Frame rate was kept at minimum 60/s. Aortic valve anatomy and flow was assessed in multiple apical views to obtain maximal flow velocity across the valve. Pulse wave Doppler flow velocity was recorded with a sample volume placed in the LV outflow tract (LVOT). LVOT diameter was measured 5 mm adjacent to the aortic valve. AVA was calculated using the continuity equation. Velocity measurements were transformed to gradients by the simplified Bernoulli equation. Mitral inflow pattern was assessed with the pulsed wave Doppler sample volume at the mitral leaflet tips and basal myocardial velocity profile recorded with pulsed wave tissue-Doppler at the medial mitral annulus. Diastolic function was classified according to guidelines.6 LV volumetric measurements and LVEF were calculated from 4- and 2-chamber using the biplane Simpson’s method. Maximal LA volume was determined before mitral valve opening and LA minimum volume before mitral valve closure. Patients were divided into 2 groups according to an echocardiographicderived normal LAVi (<35 ml/m2) and dilated LA (≥35 ml/m2).7 LA function was assessed using 2-dimensional speckle tracking analysis in the apical 4- 3-, and 2-chamber views of the LA. The semi-automated algorithm was used for drawing the region of interest between LA endocardial and epicardial borders, with manual adjustment to cover the exact thickness of the LA wall. From the average of a total of 18 segmental strain curves, global peak atrial longitudinal strain (PALS) was derived as the maximum positive strain value during systole. cMRI was performed on a Philips Ingenia 1.5T scanner with Omega HP gradient system (Philips Electronics, Koninklijke, The Netherlands). Sequential short-axis slices enclosing the entire heart were obtained during multiple breath hold sequences acquiring slices of 8-mm thickness. Delayed enhancement imaging was performed 10 to 15 minutes after administration of 0.1 mmol/kg gadoterate meglumine (Dotarem, Guerbet, Aulnay-Bois, France). Optimal inversion time (TI), to null the myocardium, was determined using a Look-Locker sequence with multiple images with varying TI. Images were analyzed blinded for clinical and echocardiographic data by an experienced examiner using Philips Intellispace software package (2.6.3.5, 2013). Ventricular chamber volumes were measured from short axis slices and LV mass was estimated by multiplying mass volume (difference in epicardial- and endocardial cross-sectional area times the sum of slice thickness gap), derived in end-diastole, by myocardial density (1.05g/ml).8 Papillary muscles were considered as part of the LV cavity and excluded from LV mass.9 Phase velocity flow mapping of flow volumes in the aorta and pulmonary trunk were used to assess stroke volume. Late enhancement pattern was reported as midwall, ischemic, and “nonspecific.” Radial and longitudinal distribution as well as segment thickness was recorded and counted using the 17segment cardiac model.10 A cycle ergometer stress test was performed on a Cardiosys system—software version 4.1 (General Electric, Freiburg, Germany). A test protocol with increments of 25 W increases every 2 minutes until exhaustion was used. Maximal
oxygen consumption rate per kilogram (VO2max) was estimated from maximal achieved watts11 and converted to metabolic equivalents. Expected VO2max was calculated from the Wasserman-Hansen equations.12 Blood was drawn from an antecubital vein after at least 10 minutes of rest. Samples were collected in ethylenediamineteraacetic acid (EDTA) tubes and stored at −80°C for later analysis of brain natriuretic peptide (BNP) using a BNP immunoassay (Abbott, Wiesbaden, Germany). A composite end point of unplanned hospital admissions (for atrial fibrillation, heart failure, or acute coronary syndrome), aortic valve replacement, and death was recorded. Decision of aortic valve replacement was done by a heartteam not participating in the study according to current guidelines.13 Follow-up for composite end point was done by review of electronic hospital records and using the Danish Civil Registration System where all deaths in Denmark are registered within 2 weeks. Follow-up was completed in August 2016. Unless otherwise stated, data are mean ± standard deviation or median (interquartile range [IQR]). Differences in normally distributed continuous variables between groups were tested using analysis of variance (ANOVA) and Wilcoxon rank-sum test was used for variables with skewed distribution. Categorical variables were tested for association with the chi-square test. Biomarker measurements were log-transformed due to a skewed distribution. Kaplan-Meier time to event models were used to generate cumulative survival curves for composite end point and groups were compared with the log-rank test. Univariable and multivariable Cox analysis adjusting for age, gender, and aortic mean gradient was used for to assess potential predictors. The proportional hazard model was validated by log-log plots to assess proportionality, and Martingale residuals were calculated and graphed, adding a smoother for assumption of linearity. A value of p <0.05 on a 2-tailed test was considered statistically significant. All tests were performed on STATA/SE statistical package 14.1 (StataCorp LP, Texas). Results Clinical data for the 92 patients enrolled is shown in Table 1. Forty-five patients (49%) had LA dilation measured by echocardiography. A diagnosis of hypertension was more frequent in the group with a dilated LA, otherwise clinical data was similar in the 2 groups. Mean arterial blood pressure was equal between LAVi groups (93 ± 10 mmHg vs 94 ± 10 mmHg, p = 0.63). BNP was higher in patients with LA dilation (60 (32 to 114) vs 43 (27 to 75), p = 0.04). Doppler-derived AVA was similar in patients with a normal and dilated LAVi (0.83 ± 0.14 vs 0.83 ± 0.17 cm2, p = 0.97; Table 2). Further, no differences in Doppler-derived peak aortic transvalvular velocity or mean gradient were found (Figure 1). Seventeen patients (81%) with LA dilation had diastolic function grade ≥2 compared with 27 (39%) patients with a normal LA (p = 0.004). Peak mitral inflow velocity (E) was higher in patients with LA dilation and E/e′ was increased (14 ± 4 vs 12 ± 5, p = 0.05; Table 2). On cMRI, patients with dilated LA had higher LV mass index (73 ± 17 vs 66 ± 16 g/m2, p = 0.03). Patients with dilated LA had increased RV volume index (70 ± 14 vs 63 ± 12 ml/m2,
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Table 1 Demographic data Left atrial volume index (ml/m2) Variable Age (years) Men Body surface area (m2) Coronary heart disease Hypertension Peripheral artery disease Diabetes mellitus Diuretic therapy Beta-blocker therapy Calcium channel blocker therapy Angiotensin inhibitor therapy Statin therapy E-GFR (ml/min)
All patients (N = 92)
<35 ml/m2 (N = 47)
≥ 35 ml/m2 (N = 45)
p-Value
74 ± 8 52 (57%) 1.86 ± 0.20 3 (3%) 63 (68%) 1 (1%) 12 (13%) 29 (32%) 13 (14%) 26 (28%) 41 (45%) 43 (47%) 75 ± 17
73 ± 7 24 (51%) 1.85 ± 0.19 1 (2%) 26 (55%) 1 (2%) 4 (9%) 16 (34%) 5 (11%) 5 (11%) 16 (34%) 21 (45%) 74 ± 15
75 ± 9 28 (62%) 1.86 ± 0.22 2 (4%) 37 (82%) 0 (0%) 8 (18%) 13 (29%) 8 (18%) 21 (47%) 25 (56%) 22 (49%) 76 ± 18
0.21 0.30 0.93 0.61 0.01 1.0 0.23 0.66 0.38 <0.001 0.06 0.84 0.63
Data are number and (%) or mean ± standard deviation. E-GFR = estimated glomerular filtration rate.
Table 2 Echocardiographic and exercise parameters according to Left atrial volume index Left atrial volume index (ml/m2) Variable ECHOCARDIOGRAPHY Left atrial volume index (ml/m2) Relative wall thickness Left ventricular mass (g) Left ventricular mass index (g/m2) Aortic valve area (cm2) Aortic valve area index (cm2/m2) Aortic valve Vmax (m/s) Aortic valve mean gradient (mmHg) E velocity (m/s) A velocity (m/s) EA-ratio Deceleration time (msec) E/e’ medial Diastolic function Peak atrial longitudinal strain (%) TAPSE (mm) S’ right ventricle (cm/s) Brain natriuretic peptide (pg/ml) EXERCISE TEST Maximal workload (Watts) % Expected VO2max Maximal workload (METS) Maximal heart rate (bpm) % Expected heart rate Maximum systolic blood pressure (mmHg)
All patients (N = 92)
<35 ml/m2 (N = 47)
≥ 35 ml/m2 (N = 45)
p-Value
36 ± 8 0.47 ± 0.08 186 ± 39 100 ± 19 0.83 ± 0.15 0.45 ± 0.08 4.20 ± 0.57 45 ± 14 0.77 ± 0.22 1.03 ± 0.30 0.78 ± 0.24 294 ± 93 13 ± 5 22/49/21/0 26 ± 6 24 ± 3 13 ± 2 51 (29–70)
29 ± 5 0.47 ± 0.07 181 ± 38 98 ± 20 0.83 ± 0.14 0.45 ± 0.08 4.11 ± 0.47 42 ± 11 0.72 ± 0.22 0.99 ± 0.28 0.75 ± 0.23 295 ± 88 12 ± 5 13/30/4/0 26 ± 5 25 ± 4 13 ± 3 43 (27–75)
43 ± 5 0.48 ± 0.08 191 ± 39 103 ± 19 0.83 ± 0.17 0.45 ± 0.09 4.30 ± 0.65 47 ± 17 0.83 ± 0.21 1.08 ± 0.31 0.81 ± 0.26 294 ± 100 14 ± 4 9/19/17/0 26 ± 7 24 ± 3 14 ± 2 60 (32–114)
0.32 0.21 0.20 0.97 0.85 0.13 0.10 0.02 0.17 0.24 0.95 0.05 0.004 0.68 0.13 0.77 0.04
115 ± 33 117 ± 23 6±2 138 ± 19 94 ± 12 177 ± 16
113 ± 31 114 ± 21 6±2 143 ± 18 97 ± 12 179 ± 15
118 ± 34 121 ± 25 6±2 133 ± 19 92 ± 12 175 ± 18
0.50 0.17 0.50 0.02 0.05 0.28
Data are number and (%) or mean ± standard deviation. TAPSE = tricuspid annular plane systolic excursion.
p = 0.01) and LV end-diastolic volume index (84 ± 18 vs 77 ± 16 ml/m2, p = 0.05) and larger right atrial volume index (52 ± 12 vs 47 ± 11 ml/m2, p = 0.03; Table 3 and Figure 1). Late gadolinium enhancement (LGE) was performed in 78 patients where 15 patients had midwall fibrosis, 3 had isch-
emic fibrosis, and 3 had nonspecific fibrosis. Overall, no difference in presence of fibrosis between LAVi groups was found (p = 0.53; Table 3). Estimated maximal oxygen peak consumption did not differ between patients with a normal and dilated LA (Table 2). Only 5 patients achieved lower than
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Figure 1. RV and LV size and LV mass and aortic mean gradient according to left atrium volume index. (A) Upper panel left—LV end-diastolic volume index between LAVi groups. (B) Upper panel right—RV end-diastolic volume index between LAVi groups. (C) Lower panel left—LV mass index between LAVi groups during peak exercise. (D) Lower panel right—Aortic mean gradient between LAVi groups. p Value: log-rank test.
Table 3 Magnetic resonance morphology according to echocardiographic-derived left atrial volume Index Left atrial volume index (ml/m2) Variable Magnetic Resonance Left ventricular end-diastolic volume index (ml/m2) Left ventricular end-systolic volume index (ml/m2) Left ventricular ejection fraction (%) Right atrial volume index (ml/m2) Right atrial emptying fraction (%) Right ventricular end-diastolic volume index (ml/m2) Right ventricular end-systolic volume index (ml/m2) Right ventricular ejection fraction (%) Left ventricular mass (g) Left ventricular mass index (g/m2) Aortic stroke volume (ml) Aortic stroke volume index (ml/m2) Aortic regurgitant fraction (%) Fibrosis* Data are number and (%) or mean ± standard deviation. * 78 patients were eligible for analysis of fibrosis.
All patients (N = 92)
< 35 ml/m2 (N = 47)
≥ 35 ml/m2 (N = 45)
p-Value
80 ± 17 31 ± 10 62 ± 7 50 ± 12 42 ± 9 66 ± 14 26 ± 7 62 ± 7 130 ± 36 69 ± 17 70 ± 18 38 ± 8 8±6 21 (27%)
77 ± 16 30 ± 10 61 ± 7 47 ± 11 43 ± 10 63 ± 12 24 ± 7 61 ± 7 122 ± 35 66 ± 16 69 ± 19 37 ± 9 7±7 9 (24%)
84 ± 18 32 ± 11 62 ± 7 52 ± 12 41 ± 9 70 ± 14 27 ± 8 62 ± 6 137 ± 37 73 ± 17 71 ± 18 38 ± 8 9±6 12 (30%)
0.05 0.44 0.37 0.03 0.48 0.01 0.15 0.51 0.05 0.03 0.66 0.68 0.15 0.53
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Table 4 Univariate and multivariate analysis of cardiac magnetic resonance parameters and echocardiographic parameters. Predictors of composite end point of death, unplanned hospitalization and aortic valve replacement Variable Cardiac Magnetic resonance Left ventricular end-diastolic volume index (ml/m2) Left ventricular end-systolic volume index (ml/ m2) Left ventricular mass index (ml/m2) Left ventricular ejection fraction (%) Right ventricular end-diastolic volume index (ml/m2) Right atrial volume index (ml/m2) Overall fibrosis Echocardiography Left atrial volume index (ml/m2) Left atrial volume index > 35 ml/m2 Aortic mean gradient (mmHg) Aortic peak velocity (m/s) Aortic valve Vmax > 4.5 m/s Aortic valve area (cm2) Brain natriuretic peptide > 125 pg/ml
HR (95% CI)
p-Value
HR (95% CI)*
p-Value
1.04 (1.02–1.06) 1.05 (1.02–1.08) 1.03 (1.01–1.05) 0.97 (0.93–1.02) 1.03 (1.01–1.06) 1.03 (1.00–1.06) 0.79 (0.32–1.94)
<0.001 0.003 0.002 0.27 0.005 0.04 0.60
1.03 (1.01–1.06) 1.04 (1.00-1-07) 1.02 (0.99–1.05) 0.97 (0.92–1.02) 1.03 (0.99–1.05 1.02 (0.99–1.05) 1.17 (0.44–3.11)
0.006 0.03 0.14 0.28 0.06 0.17 0.76
1.09 (1.04–1.14) 2.93 (1.28–6.68) 1.02 (1.00-1-04) 1.86 (1.10–3.15) 2.75 (1.26–6.01) 1.05 (0.32–3.47) 3.24 (1.35–7.77)
0.001 0.01 0.02 0.02 0.01 0.93 0.008
1.07 (1.02–1.12) 2.77 (1.19–6.46) 1.03 (1.01–1.05) † 2.17 (1.21–3.87) † 3.19 (1.44–7.06) † 0.82 (0.21–3.30) † 3.63 (1.28–10.32)
0.008 0.02 0.007 0.009 0.004 0.79 0.02
Data are number and (%) or mean ± standard deviation. * Adjusted for age, sex and aortic mean gradient. † Adjusted for age and sex only.
90% of expected estimated oxygen consumption. There was no correlation between LAVi and maximal exercise capacity (watts) but PALS correlated with maximal workload (r = 0.30, p = 0.03). During median follow-up time of 358 days, 28 events were recorded. Twenty-two patients developed symptoms and were referred for AVR, there were 4 deaths (1 sudden cardiac death) and 2 unplanned hospitalizations (1 myocardial infarction and 1 atrial fibrillation). In patients with LAVi ≥35 ml/m2, 20 patients experienced the composite end point (n = 14 AVR, n = 1 atrial fibrillation, n = 1 acute myocardial infarction) compared with 8 patients (n = 8, AVR) with normal LAVi, p = 0.008 (Figure 2 and Table 4). Apart from LAVi, BNP >125 pg/ml and LV volumes on cMRI were predictive of the composite end point, whereas LV mass index only in univariate analysis was predictive (Table 4). Discussion The present study demonstrates, in patients with severe asymptomatic AS, that LA volume assessed on conventional echocardiography is associated with more advanced LV remodeling and adverse outcome but apparently unrelated to focal myocardial fibrosis and reduced exercise capacity. AVR should be considered in asymptomatic patients with very severe AS (peak aortic jet velocity ≥5m/s), rapidly progressing disease, reduced LV ejection fraction <50%, or pathologic stress test. AS is a slowly progressive disease where myocardial hypertrophy with increased wall thickness counterbalances the increase in LV end-systolic pressure, maintaining peak systolic wall stress, and preserving an adequate stroke volume. However, the preservation of a normal cardiac output will occur at the expense of elevated LV filling pressures secondary to increased LV myocardial stiffness and diastolic dysfunction. As the LA is directly exposed to LV pressures through the open mitral valve during diastole, LA
Figure 2. Kaplan-Meier time to event analysis of predictor variables for the composite end point of unplanned hospitalization, death, and aortic valve replacement. (A) Event-free survival for the composite end point according to LAVi (35 ml/m2). (B) Event-free survival for the composite end point according to BNP >125 pg/ml. p Value: log-rank test.
size is therefore largely determined by the same factors that influence diastolic function.14 The present study demonstrates that LA dilation is frequently observed in asymptomatic patients with severe AS and associated with advanced
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diastolic dysfunction, thus supporting more advanced disease in patients with LA dilation.15,16 Although we did find an association between LV mass on cMRI and LA volume, this was relatively weak, and despite severe AS, only 29% of the population had LV hypertrophy on cMRI. In contrast a considerably stronger association was found with LV enddiastolic volume index. From a physiologic standpoint, preload can be defined as the initial stretching of cardio myocytes before contraction and is therefore closely associated with LV end diastolic volume. Thus the association between LA dilation and LV end-diastolic volume could be conceptualized to support the association between LA volume and preload. The transition from the asymptomatic state with adaptive LV hypertrophy to heart failure in AS has been suggested importantly related to development of myocardial fibrosis. Histologically and using LGE technique, fibrosis has been shown as a useful postoperative predictor for clinical outcome following AVR in symptomatic patients.17–19 However, midwall replacement fibrosis likely represents a late manifestation of the remodeling process during the course of AS.20 This could possibly explain that we only detected focal fibrosis in less than 1/3 and classic midwall fibrosis in even less. Studies have further suggested diffuse fibrosis quantitatively assessed by T1-mapping to be present even in moderate AS where it was found to be associated with LA size.21 The event rate in the present study was high but comparable with other reports.22 Data suggested that LAVi was a predictor of the composite end point in a population with severe AS. This is in agreement with other small-cohort studies of patients with severe AS, demonstrating that LA size is associated with the development of symptoms in asymptomatic patients23 and that LA size is increased among symptomatic patients.24 These findings are, however, somewhat in contrast to data from the SEAS study where LA dilation was not identified as a prognostic marker in patients with mild to moderate AS. This may reflect that, in severe AS, LAVi is a marker of changes in LV remodeling yet to occur in mild to moderate AS, and possibly other causes of LA dilation may be prevalent in the SEAS population unrelated to AS such as hypertension that would not be expected to be predictive of AVR.25 Thus, although LA size was increased, intrinsic atrial function seems relatively preserved, possibly through same mechanisms counterbalancing LV pressure overload (atrial hypertrophy). Interestingly, we were not able to demonstrate that LA function (PALS) was associated with our combined end point. In a small series of patients with AS, O’Connor and colleagues demonstrated that LA volume did not reflect the presence of intrinsic LA dysfunction, but also noted that LA emptying fraction was not different than healthy control patients.26 These findings would suggest that filling pressures seem more important than LA function in the development of symptoms in patients with severe AS. In asymptomatic AS Bergler-Klein et al. have showed that patients with a baseline BNP > 130 pg/ml were more likely to develop symptoms during follow-up,27 which is supported by this study showing a reduced event-free survival when BNP exceeds 125 pg/ml. Further, BNP was higher in patients with LA dilation. Identification of truly asymptomatic patients is difficult and some mildly symptomatic patients may have been included in the present study. However, with strenuous exercise we found maximal work capacity and estimated VO2max
achieved was normal or better in the vast majority and unrelated to LA dilation. Thus, indicating that patients were true asymptomatic with well-adapted compensatory mechanisms. Despite a high event rate the overall number of events was relatively low with a potential risk of overfitting the prognostic models. Thus, survival analyses may be associated with uncertainty. Despite this, LAVi was predictive of the composite end point, but larger prospective studies are needed before a general recommendation to use LA volume in risk stratification of patients with asymptomatic AS can be recommended. In studies of predictors of AVR the un-blinded nature of most studies are pivotal when interpreting the data due to risk of “confounding by severity.” However, heart team deciding on referral for surgery was blinded for all cMRI data and the measured LA volume index performed as part of this study. T1 mapping was not done as part of the cMRI protocol, and we can only speculate how diffuse fibrosis would have related to LA size. The present study demonstrates that LV remodeling is associated to LA size in severe asymptomatic AS. Further LAVi was despite being unrelated to exercise capacity and myocardial fibrosis, predictive of the composite end point. Morphological parameters should be emphasized as subclinical early warnings and assessed with other functional parameters during follow-up. Disclosure The authors have no conflicts of interest to disclose. 1. Ozkan A, Kapadia S, Tuzcu M, Marwick TH. Assessment of left ventricular function in aortic stenosis. Nat Rev Cardiol 2011;8:494–501. 2. Elmariah S. Patterns of left ventricular remodeling in aortic stenosis: therapeutic implications. Curr Treat Options Cardiovasc Med 2015;17:391. 3. Simek CL, Feldman MD, Haber HL, Wu CC, Jayaweera AR, Kaul S. Relationship between left ventricular wall thickness and left atrial size: comparison with other measures of diastolic function. J Am Soc Echocardiogr 1995;8:37–47. 4. Appleton CP, Galloway JM, Gonzalez MS, Gaballa M, Basnight MA. Estimation of left ventricular filling pressures using two-dimensional and Doppler echocardiography in adult patients with cardiac disease. Additional value of analyzing left atrial size, left atrial ejection fraction and the difference in duration of pulmonary venous and mitral flow velocity at atrial contraction. J Am Coll Cardiol 1993;22:1972–1982. 5. Nishimura RA, Otto CM, Bonow RO, Carabello BA, Erwin JP 3rd, Guyton RA, O’Gara PT, Ruiz CE, Skubas NJ, Sorajja P, Sundt TM 3rd, Thomas JD, Anderson JL, Halperin JL, Albert NM, Bozkurt B, Brindis RG, Creager MA, Curtis LH, DeMets D, Guyton RA, Hochman JS, Kovacs RJ, Ohman EM, Pressler SJ, Sellke FW, Shen WK, Stevenson WG, Yancy CW. 2014 AHA/ACC guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Thorac Cardiovasc Surg 2014;148:e1–e132. 6. Nagueh SF, Smiseth OA, Appleton CP, Byrd BF 3rd, Dokainish H, Edvardsen T, Flachskampf FA, Gillebert TC, Klein AL, Lancellotti P, Marino P, Oh JK, Popescu BA, Waggoner AD. Recommendations for the evaluation of left ventricular diastolic function by echocardiography: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr 2016;29:277–314. 7. Lang RM, Badano LP, Mor-Avi V, Afilalo J, Armstrong A, Ernande L, Flachskampf FA, Foster E, Goldstein SA, Kuznetsova T, Lancellotti P, Muraru D, Picard MH, Rietzschel ER, Rudski L, Spencer KT, Tsang W, Voigt JU. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Eur Heart J Cardiovasc Imaging 2015;16:233–270.
Valvular Heart Disease/Left Atrial Dilation in Aortic Stenosis 8. Schulz-Menger J, Bluemke DA, Bremerich J, Flamm SD, Fogel MA, Friedrich MG, Kim RJ, von Knobelsdorff-Brenkenhoff F, Kramer CM, Pennell DJ, Plein S, Nagel E. Standardized image interpretation and post processing in cardiovascular magnetic resonance: Society for Cardiovascular Magnetic Resonance (SCMR) board of trustees task force on standardized post processing. J Cardiovasc Magn Reson 2013;15:35. 9. Kawel-Boehm N, Maceira A, Valsangiacomo-Buechel ER, VogelClaussen J, Turkbey EB, Williams R, Plein S, Tee M, Eng J, Bluemke DA. Normal values for cardiovascular magnetic resonance in adults and children. J Cardiovasc Magn Reson 2015;17:29. 10. Cerqueira MD, Weissman NJ, Dilsizian V, Jacobs AK, Kaul S, Laskey WK, Pennell DJ, Rumberger JA, Ryan T, Verani MS. Standardized myocardial segmentation and nomenclature for tomographic imaging of the heart. A statement for healthcare professionals from the Cardiac Imaging Committee of the Council on Clinical Cardiology of the American Heart Association. Int J Cardiovasc Imaging 2002;18:539–542. 11. Astrand PO. Quantification of exercise capability and evaluation of physical capacity in man. Prog Cardiovasc Dis 1976;19:51–67. 12. Guazzi M, Adams V, Conraads V, Halle M, Mezzani A, Vanhees L, Arena R, Fletcher GF, Forman DE, Kitzman DW, Lavie CJ, Myers J. EACPR/AHA Scientific Statement. Clinical recommendations for cardiopulmonary exercise testing data assessment in specific patient populations. Circulation 2012;126:2261–2274. 13. Vahanian A, Alfieri O, Andreotti F, Antunes MJ, Baron-Esquivias G, Baumgartner H, Borger MA, Carrel TP, De Bonis M, Evangelista A, Falk V, Iung B, Lancellotti P, Pierard L, Price S, Schafers HJ, Schuler G, Stepinska J, Swedberg K, Takkenberg J, Von Oppell UO, Windecker S, Zamorano JL, Zembala M. Guidelines on the management of valvular heart disease (version 2012). Eur Heart J 2012;33:2451–2496. 14. Matsuda M, Matsuda Y. Mechanism of left atrial enlargement related to ventricular diastolic impairment in hypertension. Clin Cardiol 1996;19:954–959. 15. Pritchett AM, Mahoney DW, Jacobsen SJ, Rodeheffer RJ, Karon BL, Redfield MM. Diastolic dysfunction and left atrial volume: a populationbased study. J Am Coll Cardiol 2005;45:87–92. 16. Aljaroudi W, Alraies MC, Halley C, Rodriguez L, Grimm RA, Thomas JD, Jaber WA. Impact of progression of diastolic dysfunction on mortality in patients with normal ejection fraction. Circulation 2012;125:782– 788. 17. Milano AD, Faggian G, Dodonov M, Golia G, Tomezzoli A, Bortolotti U, Mazzucco A. Prognostic value of myocardial fibrosis in patients with
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