Determinants of left atrial volume index in patients with aortic stenosis: A multicentre pilot study

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Archives of Cardiovascular Disease (2017) xxx, xxx—xxx

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CLINICAL RESEARCH

Determinants of left atrial volume index in patients with aortic stenosis: A multicentre pilot study Facteurs déterminants du volume indexé de l’oreillette gauche chez les patients porteurs d’un rétrécissement aortique : étude pilote multicentrique Dan Rusinaru a,b,1, Yohann Bohbot a,1, Erwan Salaun c, Erwan Donal d,e, Anne-Claire Calsata c, Elena Galli d,e, Cécile Lavoute c, Maxime Fournet d,e, Catherine Szymanski a, Christophe Leclercq d,e, Gilbert Habib c, Christophe Tribouilloy a,b,∗ a

Cardiology department, university hospital of Amiens, avenue René-Laënnec, 80054 Amiens cedex 1, France b Inserm U-1088, Jules Verne university of Picardie, 80054 Amiens, France c Cardiology department, university hospital La Timone, 13005 Marseille, France d Cardiology department & CIC-IT 1414, hôpital Pontchaillou, university hospital of Rennes, 35033 Rennes, France e LTSI UMR 1099, university Rennes-1, 35033 Rennes, France Received 11 August 2016; received in revised form 5 December 2016; accepted 19 December 2016

KEYWORDS Aortic stenosis; Left atrial volume; Echocardiography; Outcome

Summary Background. — Left atrial (LA) enlargement is frequent in patients with aortic stenosis (AS), yet its determinants and prognostic implications are poorly understood. Aims. — To identify the echocardiographic variables associated with increased LA volume index (LAVI), and test the prognostic value of LAVI in AS.

Abbreviations: AS, Aortic stenosis; CI, Confidence interval; HR, Hazard ratio; LA, Left atrial; LAVI, Left atrial volume index; LV, Left ventricular. ∗ Corresponding author. Cardiology department, university hospital of Amiens, avenue René-Laënnec, 80054 Amiens cedex 1, France. E-mail address: [email protected] (C. Tribouilloy). 1 Dan Rusinaru and Yohann Bohbot contributed equally to this work. http://dx.doi.org/10.1016/j.acvd.2016.12.016 1875-2136/© 2017 Elsevier Masson SAS. All rights reserved.

Please cite this article in press as: Rusinaru D, et al. Determinants of left atrial volume index in patients with aortic stenosis: A multicentre pilot study. Arch Cardiovasc Dis (2017), http://dx.doi.org/10.1016/j.acvd.2016.12.016

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D. Rusinaru et al. Methods. — We prospectively included 715 patients with AS in sinus rhythm at enrolment. Echocardiography was performed at baseline. Median follow-up was 22.0 (9—34) months. Patients were divided into two groups according to the best cut-off for event prediction during follow-up (45 mL/m2 ). Results. — Compared with LAVI < 45 mL/m2 , patients with LAVI ≥ 45 mL/m2 had a lower stroke volume, cardiac output and left ventricular (LV) ejection fraction, greater LV volumes and mass and higher filling pressures. By linear regression, LAVI was best correlated with E wave mitral velocity (r = 0.34), E/A ratio (r = 0.34), E/e’ ratio (r = 0.28), indexed LV mass (r = 0.29), systolic pulmonary artery pressure (r = 0.34) and LV longitudinal strain (r = —0.28). Multivariable analysis confirmed the independent association of LAVI with age (P < 0.001), indexed aortic valve area (P = 0.04), indexed LV mass (P < 0.001), LV ejection fraction (P = 0.007), LV end-diastolic volume (P = 0.001), E/A ratio (P < 0.001) and E/e’ ratio (P < 0.001). LAVI ≥ 45 mL/m2 was independently predictive of the combined endpoint of cardiovascular death or hospitalization for heart failure (adjusted hazard ratio 1.69, 95% confidence interval 1.04—2.73). Conclusion. — LA enlargement is correlated with AS severity, but also with variables reflecting LV systolic and diastolic dysfunction. Further studies are needed to investigate the outcome implication of LA enlargement in patients with AS. © 2017 Elsevier Masson SAS. All rights reserved.

MOTS CLÉS Rétrécissement aortique ; Volume de l’oreillette gauche ; Échocardiographie ; Pronostic

Résumé Background. — La dilatation de l’oreillette gauche (OG) est fréquente chez les patients porteurs d’un rétrécissement aortique (RA), mais ses facteurs déterminants et sa valeur pronostique ne sont pas clairement définis. Objectif. — Le but de cette étude est d’identifier les paramètres échographiques associés avec l’augmentation du volume indexé de l’oreillette gauche (VOG) et de tester la valeur pronostique de ce dernier chez les patients atteints d’un RA. Méthodes. — Nous avons inclus de fac ¸on prospective 715 patients porteurs d’un RA en rythme sinusal. L’échocardiographie a été réalisée à l’entrée dans l’étude. Le suivi médian était de 22 (9—34) mois. Les patients on été divisés en 2 groupes selon le meilleur seuil identifié pour la prédiction des événements pendant le suivi (45 mL/m2 ). Résultats. — En comparaison avec le groupe VOG < 45 mL/m2 , le groupe VOG ≥ 45 mL/m2 était caractérisé par une réduction du volume d’éjection systolique, du débit cardiaque et de la fraction d’éjection et par une augmentation de la masse et des volumes ventriculaires gauches (VG), ainsi que des pressions de remplissage. Par régression linéaire, le VOG était mieux corrélé avec la vitesse maximale de l’onde E mitrale (r = 0,34), le rapport E/A (r = 0,34), le rapport E/e’ (r = 0,28), la masse VG indexée (r = 0,29), la pression systolique pulmonaire (r = 0,34) et le strain VG (r = —0,28). L’analyse multivariée confirmait l’association indépendante entre VOG et les paramètres suivants: age (p < 0,001), surface valvulaire aortique indexée (p = 0,04), masse VG indexée (p < 0,001), fraction d’éjection (p = 0,007), volume télédiastolique VG (p = 0,001), rapport E/A (p < 0,001) et rapport E/e’ (p < 0,001). VOG ≥ 45 mL/m2 était un facteur prédictif indépendant du critère combiné regroupant décès de cause cardiovasculaire et hospitalisation pour insuffisance cardiaque au cours du suivi (risque relatif ajusté 1,69, IC 95 % 1,04—2,73). Conclusion. — La dilatation de l’OG est corrélée avec la sévérité de l’obstacle valvulaire aortique mais également avec la fonction systolique et diastolique VG. De plus amples études sont nécessaires pour étudier l’impact pronostique du VOG chez les patients atteints d’un RA. © 2017 Elsevier Masson SAS. Tous droits r´ eserv´ es.

Background Aortic stenosis (AS) is the most common valvular heart disease in developed countries, and its prevalence reaches about 15% of patients aged > 75 years [1]. Classical symptoms of AS are observed at an advanced stage of the disease [2].

Current guidelines recommend aortic valve replacement for severe AS in symptomatic or asymptomatic patients when there is left ventricular (LV) function impairment (LV ejection fraction < 50%) [3]. However, reduction in LV ejection fraction is a late event in the natural history of AS, and most patients with severe AS have a normal LV ejection fraction,

Please cite this article in press as: Rusinaru D, et al. Determinants of left atrial volume index in patients with aortic stenosis: A multicentre pilot study. Arch Cardiovasc Dis (2017), http://dx.doi.org/10.1016/j.acvd.2016.12.016

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Left atrial volume index in aortic stenosis even when symptoms are present. Conversely, LV hypertrophy and abnormal LV diastolic function are common findings in these patients before LV ejection fraction impairment occurs [4—6]. Left atrial (LA) enlargement is a recognized marker of increased LV filling pressures [7], and is frequent in patients with severe AS [8,9], so that in the absence of mitral valve disease or atrial fibrillation, it reflects the severity and duration of the disease [10]. LA size is associated with poor prognosis in the general population and in patients with heart failure [11—13]. Some studies have suggested that in severe AS, LA enlargement estimated by the anteroposterior diameter is a marker of increased mortality [14,15], even after aortic valve replacement. Although M-mode LA dimension is easy to acquire, reproducible and used in clinical practice, its validity has been challenged [16]. Given that LA is an asymmetrical cavity, LA enlargement is more accurately reflected by a volume measurement, rather than an area or a linear dimension [16,17]. In addition, in the general population the strength of the relationship between the occurrence of cardiovascular diseases and LA size is stronger for LA volume than for linear dimensions [18,19]. Moreover, LA volume estimated by two-dimensional echocardiography is closely correlated with computed tomography [20] and three-dimensional echocardiography [21] measurements. The present prospective study includes patients diagnosed with AS at the echocardiography laboratories of three tertiary centres in France (university hospital of Amiens, Marseille and Rennes) who were in sinus rhythm at the time of the baseline echocardiography. The aims of the study were two-fold: to identify the echocardiographic variables associated with LA enlargement in AS; and to evaluate the potential prognostic impact of left atrial volume index (LAVI) in patients with AS.

Methods Inclusion criteria Between 2011 and 2015, patients aged ≥ 18 years and diagnosed with AS (aortic leaflet calcifications with reduction in systolic movements and peak aortic jet velocity > 2.5 m/s) were prospectively identified and included in an electronic database. The following patients were excluded: patients with > mild aortic and/or mitral regurgitation; patients with mitral stenosis; patients with prosthetic valves, congenital heart disease, supravalvular or subvalvular AS or dynamic LV outflow tract obstruction; and patients who refused to participate in the study. A total of 885 patients were enrolled: 150 were subsequently excluded because of atrial fibrillation on the baseline electrocardiogram; and 20 patients were excluded because of missing data. Finally, 715 patients were included. Fig. 1 depicts the selection of patients before inclusion. The study was conducted in accordance with institutional policies, national legislation and the revised Helsinki declaration.

Clinical and biological variables We collected clinical and demographic baseline characteristics, including cardiovascular risk factors, presence

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Figure 1. Flow-chart depicting the selection of patients before inclusion in the study. AS: aortic stenosis.

of symptoms, comorbidity status and presence of coronary artery disease (documented history of acute coronary syndromes, coronary revascularization or coronary artery disease previously confirmed by coronary angiography: reduction of the normal diameter ≥ 50% in the left main coronary artery and ≥ 70% in the right coronary, left anterior descending and circumflex arteries). Blood pressure and heart rate were measured for all patients at the time of echocardiography. The glomerular filtration rate, estimated by the Cockcroft calculator, was collected in 562 patients, and B-type natriuretic peptide concentration was measured in 329 patients.

Echocardiography All patients underwent a comprehensive Doppler echocardiography study, using commercially available ultrasound systems. Three cardiac cycles were averaged for all measures. Aortic valve area was calculated by using the continuity equation. The LV outflow tract was measured in the parasternal long-axis view with zoom on the aortic valve. The LV outflow tract time-velocity integral was measured in the apical five-chamber view. Mean aortic valve gradient and peak aortic jet velocity were measured in multiple acoustic windows (apical five-chamber, suprasternal, right parasternal and epigastric), and the highest recorded value was taken into account. LV ejection fraction was measured by Simpson’s biplane method. LV internal diameters and wall thickness were measured at end-diastole and end-systole in the parasternal long-axis view [22], and LV mass was calculated using an anatomically validated formula [23]. Stroke volume was calculated by multiplying the LV outflow tract

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D. Rusinaru et al.

area by the LV outflow tract time velocity integral, and cardiac output was calculated by multiplying it with the heart rate. LA volume was measured in LV end-systole by the Simpson’s biplane method in apical two- and four-chamber views [17,22]. LV filling pressure was estimated by the mitral peak Doppler E wave to peak mitral annulus velocity ratio (E/e’) [24]. Systolic pulmonary artery pressure was recorded from the maximum peak tricuspid regurgitation velocity in any view, using the simplified Bernoulli equation. Right atrial pressure was estimated from the inspiratory collapse of the inferior vena cava [25]. Global LV longitudinal strain was measured in 503 of 715 patients using EchoPAC software (GE Vivid 9 Expert; GE Healthcare, Little Chalfont, UK) in four-, three- and two-chamber views [26].

Follow-up Patients were followed for 22 (9—34) months. For the outcome analysis, we used a primary composite endpoint of cardiovascular mortality or hospitalization for heart failure after diagnosis starting at the baseline echocardiography. The secondary endpoint was all-cause mortality. Patients were followed by clinical consultations and echocardiography in the outpatient clinics of the three tertiary centres. A few patients were followed in public hospitals or private practices by referring cardiologists working in collaboration with the tertiary centres. Cause of death was ascertained by hospital records, death certificates and autopsy records, or by contacting the patient’s physician or referring cardiologist. Cardiovascular death was considered as one of the following: sudden death, heart failure-related death, acute myocardial infarction death or other cardiovascular death (cerebrovascular events, renal and abdominal vascular events, aortic dissection and pulmonary embolism).

Statistical analysis SPSS software, version 18.0 (IBM, Armonk, NY, USA) was used for statistical analysis. By receiver operating characteristic curve analysis followed by Youden’s test, the best LAVI cut-off for the prediction of cardiovascular events during follow-up was 45 mL/m2 . The study population was therefore divided into two groups (< 45 mL/m2 and ≥ 45 mL/m2 ). Continuous variables with normal distribution are expressed as means ± standard deviations, whereas continuous variables with a skewed distribution are reported as medians (interquartile ranges). Categorical variables are expressed as frequencies and counts. The ␹2 test was used to compare categorical variables between groups. The independentsample t test or the Mann-Whitney U test was used to compare continuous variables with normal or skewed distribution between groups. Univariate correlations were evaluated by Pearson’s correlation coefficient. Age, sex and all covariates highly associated with LAVI on univariate analysis (P < 0.001) were included in the multiple regression analysis. Variables independently associated with LAVI were identified in multiple linear regression analysis with backward elimination and colinearity diagnostic. Univariate and multivariable analyses of time to events were performed using Cox proportional hazards models, with LAVI as an independent variable in categorical format. Kaplan-Meier survival estimates were compared using a log-rank test. The

multivariable model was adjusted for age, symptoms, coronary artery disease, LV ejection fraction, aortic valve area and aortic valve surgery (as a time-dependent variable). A P-value < 0.05 was considered statistically significant. All P-values are results of two-tailed tests.

Results Baseline characteristics The study population consisted of 715 patients (Table 1). Median age was 77 (69—83) years, 54% were men, and more than two-thirds had symptoms at baseline. More than 60% of patients had a history of hypertension, 46% had dyslipidaemia and 24% were diabetic. Coronary artery disease was diagnosed in about 20% of cases. Approximately two-thirds of patients with AS included in the study had some degree of LA enlargement (defined by a LAVI cut-off of 34 mL/m2 according to the recommendations for chamber quantification [22]). The study groups (LAVI < 45 mL/m2 and LAVI ≥ 45 mL/m2 ) showed no difference with regard to sex or history of hypertension, dyslipidaemia, diabetes and smoking. Patients with LAVI < 45 mL/m2 were younger, more often overweight and had a greater body surface area. Patients with LAVI ≥ 45 mL/m2 more often had symptoms, coronary artery disease, a lower estimated glomerular filtration rate and a higher B-type natriuretic peptide concentration (Table 1).

Echocardiographic predictors of LAVI Table 2 compares the variables collected at the baseline echocardiography for the two study groups. The aortic valve area was lower for patients with LAVI ≥ 45 mL/m2 . There were no significant differences between the two groups in terms of peak aortic jet velocity and mean pressure gradient. Compared with patients with LAVI < 45 mL/m2 , patients with LAVI ≥ 45 mL/m2 had lower LV outflow tract timevelocity integral, stroke volume, indexed stroke volume and cardiac output, and greater LV dimensions and volumes (Table 2). Patients with LAVI ≥ 45 mL/m2 had lower LV ejection fraction and greater indexed LV mass than patients with LAVI < 45 mL/m2 . Left (greater E mitral wave velocity, E/A ratio and E/e’ ratio and shorter E wave deceleration time) and right (greater systolic pulmonary artery pressure) ventricular filling pressures were significantly increased in the group with LAVI ≥ 45 mL/m2 (Table 2). For the 503 patients in whom global LV longitudinal strain measurements were available, there was a significant inverse relationship with LAVI. Linear regression analysis between echocardiography variables and LAVI (Table 3) showed significant yet moderate correlations with aortic valve area, LV outflow tract time-velocity integral, stroke volume, cardiac output, LV volumes and diameters, LV ejection fraction, LV mass, E wave velocity, E/A and E/e’ ratios, E wave deceleration time and systolic pulmonary artery pressure. The best correlations were with E wave mitral velocity (r = 0.34), E/A ratio (r = 0.34), E/e’ ratio (r = 0.28), indexed LV mass (r = 0.29) and systolic pulmonary artery pressure (r = 0.34). Multivariable linear regression analysis (Table 4) confirmed the

Please cite this article in press as: Rusinaru D, et al. Determinants of left atrial volume index in patients with aortic stenosis: A multicentre pilot study. Arch Cardiovasc Dis (2017), http://dx.doi.org/10.1016/j.acvd.2016.12.016

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Table 1 Baseline demographic, clinical and biological characteristics of the study patients, overall and according to left atrial volume index. Variable

Demographics and symptomatic status Age (years)

Overall population (n = 715)

LAVI < 45 mL/m2 (n = 394)

LAVI ≥ 45 mL/m2 (n = 321)

P

77 (69—83)

75 (67—82) 211 (53.6) 74 (64—84) 1.82 ± 0.2 140 (128—150) 270 (68.5) 36 (9.2) 43 (10.9)

79 (70—84) 177 (55.1) 70 (60—81) 1.78 ± 0.2 134 (120—150) 267 (83.2) 36 (11.3) 30 (9.4)

< 0.001

137 (34.8) 190 (48.2) 67 (17.0)

69 (21.5) 173 (53.9) 79 (24.6)

243 (61.8) 91 (23.2) 87 (22.2) 190 (48.3) 64 (16.2)

204 (63.9) 65 (20.4) 82 (25.8) 138 (43.3) 81 (25.2)

66 (48—84) 123 (60-221)

57 (39—78) 222 (97-555)

Men

388 (54.3)

Weight (kg)

73 (63—83)

Body surface area (m2 ) Systolic blood pressure (mmHg)

1.8 ± 0.2 140 (121—150) .537 (75.1)

Symptoms Angina Syncope NYHA class I II III—IV Medical history and risk factors Hypertension Smoking Diabetes mellitus Dyslipidaemia Coronary artery disease Laboratory variables Estimated glomerular filtration rate (mL/min)a B-type natriuretic peptide concentration (pg/mL)b

72 (10.1) 73 (10.3) 206 (28.8) 363 (50.8) 146(20.4) 447 (62.8) 156 (21.9) 169 (23.8) 328 (46.1) 145 (20.3) 62 (42—81) 147 (73-328)

0.36 0.01 0.03 0.007 < 0.001 0.21 0.29 < 0.001

0.31 0.21 0.15 0.10 0.002 0.002 < 0.001

Data are expressed as median (interquartile range), number (%) or mean ± standard deviation. LAVI: left atrial volume index. a Available in 562 patients. b Available in 329 patients.

independent association of LAVI with age (P < 0.001), indexed aortic valve area (P = 0.04), indexed LV mass (P < 0.001), LV ejection fraction (P = 0.007), LV end-diastolic volume (P = 0.001), E/A ratio (P < 0.001) and E/e’ ratio (P < 0.001). For patients in whom global LV longitudinal strain measurements were available, LAVI was significantly correlated with global LV longitudinal strain (r = —0.28; Table 3). Multivariable analysis (Table 4) confirmed that LAVI was independently related to age (P < 0.001), indexed aortic valve area (P = 0.045), indexed LV mass (P < 0.001), global LV longitudinal strain (P = 0.03) and E/e’ ratio (P < 0.001).

Outcome implication of LAVI During follow-up, 72 events (34 deaths with cardiac causes and 38 hospital admissions for heart failure) were recorded.

Median follow-up was 22.0 (9—34) months, and 52% of patients were operated on during follow-up. In patients who underwent surgery (369 patients), aortic bioprostheses were used in 87% of cases (n = 322), and 63 patients (17%) had at least one associated coronary artery bypass graft at the time of surgery. Two-year event-free survival (free from hospitalization for heart failure or cardiovascular death after diagnosis) was 83 ± 2% for LAVI ≥ 45 mL/m2 and 92 ± 2% for LAVI < 45 mL/m2 (log-rank P = 0.001; Fig. 2). On univariate Cox analysis, the risk of events increased with LAVI (hazard ratio [HR] 2.15, 95% confidence interval [CI] 1.34—3.43 for LAVI ≥ 45 mL/m2 versus < 45 mL/m2 ; P = 0.001). The relationship remained unchanged after adjustment for covariates of prognostic importance (adjusted HR 1.69, 95% CI 1.04—2.73; P = 0.034). The risk of all-cause death was not associated with LAVI enlargement on univariate analysis (HR 1.51,

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D. Rusinaru et al. Table 2

Echocardiographic variables overall and according to left atrial volume index.

Variable

Overall population (n = 715)

LAVI < 45 mL/m2 (n = 394)

LAVI ≥ 45 mL/m2 (n = 321)

P

Aortic valve area (cm2 )

0.79 (0.63—0.95) 0.44 (0.36—0.53) 4.2 (3.7—4.7) 46 (35—58)

0.81 (0.66—1.01) 0.45 (0.36—0.55) 4.3 (3.8—4.7) 48 (36—58)

0.74(0.60—0.90)

< 0.001

0.42 (0.34—0.51) 4.2 (3.7—4.7) 45 (34—58)

< 0.001

0.35

22 (19—26)

23 (19—26)

21 (18—25)

0.006

79 (66—94) 44 (37—52)

80 (69—95) 45 (38—52)

77 (64—91) 44 (36—51)

0.007 0.05

5.6 (4.7—6.8) 49 (45—54)

5.8 (4.9—6.9) 48 (44—52)

5.5 (4.5—6.4) 50 (45—56)

0.001 < 0.001

30 (26—36)

28 (25—35)

32 (26—38)

< 0.001

13 (11—15)

13 (11—15)

13 (12—15)

0.07

62 (54—68) 131 (106—158) 105 (82—132) 39 (26—55) 58 (47—73)

64 (57—69) 122 (99—145) 100 (80—126) 36 (26—48) 56 (45—67)

60 (50—65) 144 (116—172) 110 (86—138) 45 (30—63) 60 (49—80)

< 0.001 < 0.001

22 (15—30)

20 (14—27)

25 (17—36)

< 0.001

85 (67—110) 0.82 (0.65—1.1) 221 (176—286) 12.7 (9—17.4) 33 (27—42) —14.4 ± 4.3

78 (64—98)

98 (73—123) 0.95 (0.68—1.7) 209 (165—282) 14.4 (9.2—20.8) 36 (29—46) —13.3 ± 4

< 0.001

Indexed aortic valve area (cm2 /m2 ) Peak aortic jet velocity (m/s) Transaortic mean pressure gradient (mmHg) LV outflow tract velocity time integral (cm) Stroke volume (mL) Indexed stroke volume (mL/m2 ) Cardiac output (L/min) LV end-diastolic diameter (mm) LV end-systolic diameter (mm) LV end-diastolic septum thickness (mm) LV ejection fraction (%) Indexed LV mass (g/m2 ) LV end-diastolic volume (mL) LV end-systolic volume (mL) Indexed LV end-diastolic volume (mL/m2 ) Indexed LV end-systolic volume (mL/m2 ) E mitral velocity (cm/s) E/A E deceleration time (ms) E/e’ sPAP (mmHg) GLS (%)a

0.74 (0.62—0.95) 235 (188—289) 11.6 (8.8—16) 31 (25—38) —15.6 ± 4

0.56

< 0.001 < 0.001 < 0.001

< 0.001 < 0.001 < 0.001 < 0.001 < 0.001

Data are expressed as median (interquartile range) or mean ± standard deviation. A: late mitral inflow wave; E: early mitral inflow wave; E/e’: mitral peak Doppler E wave to peak mitral annulus velocity ratio; GLS: global longitudinal strain; LAVI: left atrial volume index; LV: left ventricular; sPAP: systolic pulmonary artery pressure. a Available in 503 patients.

95% CI 0.98—3.10 for LAVI ≥ 45 mL/m2 versus < 45 mL/m2 ; P = 0.10) or multivariable analysis (adjusted HR 1.21, 95% CI 0.80—2.55 for LAVI ≥ 45 mL/m2 versus < 45 mL/m2 ; P = 0.32). LAVI ≥ 45 mL/m2 was not associated with a greater risk of hospital admission for heart failure during follow-up (adjusted HR 1.12, 95% CI 0.71—2.91; P = 0.56).

Discussion This multicenter prospective study shows that LA enlargement is frequently observed in patients with AS. LA enlargement is correlated with the severity of the AS on the one hand, and with variables reflecting the systolic and

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Table 3 Univariate covariates of left atrial volume index by linear regression analysis. Variable 2

Aortic valve area (cm ) Indexed aortic valve area (cm2 /m2 ) Peak aortic jet velocity (m/s) Transaortic mean pressure gradient (mmHg) LV outflow tract velocity time integral (cm) Indexed stroke volume (mL/m2 ) Cardiac index (L/min/m2 ) LV end-diastolic diameter (mm) LV end-systolic diameter (mm) LV end-diastolic septum thickness (mm) LV ejection fraction (%) Indexed LV mass (g/m2 ) LV end-diastolic volume (mL) LV end-systolic volume (mL) Indexed LV end-diastolic volume (mL/m2 ) Indexed LV end-systolic volume (mL/m2 ) E mitral velocity (cm/s) E/A E deceleration time (ms) E/e’ sPAP GLSa

r

P

—0.21 —0.18

< 0.001 < 0.001

0.03 0.03

0.36 0.36

—0.10

0.01

—0.09

0.02

—0.20 0.23

< 0.001 < 0.001

0.22

< 0.001

0.03

0.49

—0.17 0.29 0.21 0.24 0.26

< 0.001 < 0.001 < 0.001 < 0.001 < 0.001

0.27

< 0.001

0.34 0.34 —0.11 0.28 0.34 —0.28

< 0.001 < 0.001 0.01 < 0.001 < 0.001 < 0.001

A: late mitral inflow wave; E: early mitral inflow wave; E/e’: mitral peak Doppler E wave to peak mitral annulus velocity ratio; GLS: global longitudinal strain; LV: left ventricular; sPAP: systolic pulmonary artery pressure. a Available in 503 patients.

diastolic performance of the LV on the other. Therefore, in patients with AS, LA enlargement represents an indicator of both the severity and history of the disease. Moreover, this study suggests the potential impact of LAVI on the occurrence of events in patients with AS. We observed that LAVI had an impact on the combined risk of cardiovascular mortality or hospitalization for heart failure. However, the relationship between LAVI and all-cause death was not significant, presumably because of the small number of events and the short follow-up. LA volume is an objective, accurate and reproducible variable that is easily obtained in most patients, and is relatively preload independent [7]; moreover, it does not vary with heart rate and respiration. LA enlargement is an independent long-term predictor of cardiovascular events in the general population [27], and LAVI is associated with an increased risk of all-cause death in patients with normal LV filling pressures and preserved LV ejection fraction

Table 4 Independent covariates of left atrial volume index identified by multivariable linear regression analysis. Multiple R2 of the model Model 1 Age (years) Indexed aortic valve area (cm2 /m2 ) LV ejection fraction (%) Indexed LV end-diastolic volume (mL/m2 ) E/A E/e’ Indexed LV mass (g/m2 ) Model 2 Age (years) Indexed aortic valve area (cm2 /m2 ) GLS (%) E/e’ Indexed LV mass (g/m2 )

Beta coefficients

P

0.20 —0.08

< 0.001 0.04

—0.15

0.007

0.18

0.001

0.24 0.26 0.21

< 0.001 < 0.001 < 0.001

0.18 —0.08

< 0.001 0.045

—0.10 0.20 0.23

0.03 < 0.001 < 0.001

0.39

0.43

Model 1 includes age, sex, indexed aortic valve area, indexed LVV mass, indexed LV end-systolic and end-diastolic volumes, E/A ratio, E/e’ ratio, LV ejection fraction, cardiac index and systolic pulmonary artery pressure as covariates; model 2 includes, on top of these, GLS. A: late mitral inflow wave; E: early mitral inflow wave; E/e’: mitral peak Doppler E wave to peak mitral annulus velocity ratio; GLS: global longitudinal strain; LV: left ventricular.

[12]. LA enlargement is linked with an increased incidence of heart failure, and the relationship is independent of age, history of myocardial infarction, diabetes mellitus, hypertension, LV hypertrophy and mitral inflow velocities [28,29]. In patients with heart failure [28], LAVI may be useful for risk stratification because it is an independent predictor of adverse cardiac events [30]. Increased LA volume is also a predictor of stroke [31] and a predictor of death after acute myocardial infarction, where an exponential increase in mortality with increasing LA volume has been documented [32]. Lately, LAVI has been studied in valvular heart disease, especially in organic mitral regurgitation. In organic mitral regurgitation in sinus rhythm, LAVI predicts long-term outcome [33], and should be measured in routine clinical practice for risk stratification and clinical decision-making [3]. Very few reports have explored LA enlargement in AS, and most of them (focused on LA diameter) have been limited to the assessment of postoperative outcome. One study found that a greater preoperative LA diameter predicts poor

Please cite this article in press as: Rusinaru D, et al. Determinants of left atrial volume index in patients with aortic stenosis: A multicentre pilot study. Arch Cardiovasc Dis (2017), http://dx.doi.org/10.1016/j.acvd.2016.12.016

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D. Rusinaru et al. The outcome implication of LAVI in the setting of AS remains poorly defined [14]. Our results suggest a link between LA enlargement and a greater risk of cardiac events during follow-up in patients with AS managed medically and surgically. Such a relationship seems logical, given the correlation between LAVI and both the severity of the valvular obstacle and LV myocardial performance, but requires additional large studies for confirmation.

Study limitations There were some limitations to our study. The follow-up was short so the number of events was low, and there were also some missing data. This explains, in our opinion, why we could not demonstrate a link between LAVI and all-cause death. The strength of the association between LAVI and the echocardiography variables was moderate, as all correlation coefficients resulting from linear regression analyses were < 0.5, suggesting high significance, but not strong correlation. We could not analyse the prognostic impact of atrial fibrillation occurring during follow-up, as this information was not recorded. Moreover, in routine practice, the assessment of LAVI is not feasible in a minority of patients because of a poor acoustic window. Figure 2. Kaplan-Meier curves of survival free of events for patients with left atrial volume index (LAVI) < and ≥ 45 mL/m2 .

symptomatic improvement after aortic valve replacement [34]. A link between LA diameter and mortality or development of symptoms in asymptomatic patients with severe AS has been suggested [15]. Another study suggested that LA diameter is associated with decreased long-term survival [14], even after valve replacement. Dalsgaard et al. [8] found that in patients with asymptomatic AS and peak aortic jet velocity between 2.5 and 4 m/s, LAVI is correlated to aortic valve area, LV mass, LV end diastolic volume and the presence of a restrictive filling pattern, but not to LV ejection fraction. Our analysis shows that LAVI is correlated to aortic valve area, but not to peak aortic jet velocity or mean pressure gradient. We can assume that this lack of relationship is explained by the decrease in flow variables (cardiac output, stroke volume and LV ejection fraction) in patients with an enlarged left atrium. In the present report, LAVI was also related to all variables of LV function, such as end-diastolic and end-systolic diameters and volumes, LV mass and global LV longitudinal strain. E wave mitral velocity, E/A ratio and E/e’ ratio showed correlation with LAVI, all these variables reflecting LV filling pressure. Indeed, LA size has been called the ‘‘haemoglobin A1C’’ of left-sided heart disease [7]. The increase in LA volume is a reflection of elevated LV filling pressures in the absence of congenital heart disease, mitral valve or primary atrial pathology. In a non-compliant left ventricle, as the LA is exposed to the pressures of the LV during diastole, LA pressure rises to maintain adequate LV filling [35]; the chronically elevated LA wall tension leads to chamber dilatation. LA volume is therefore an expression of the chronicity of exposure to abnormal filling pressures [10]. We recently reported [36] that one of the best determinants of atrial fibrillation in AS is LA volume.

Conclusions Our results shows that in patients with AS, LAVI is related to aortic valve area and to LV systolic and diastolic variables, so that it reflects the severity and consequences of the AS, but more particularly the history or duration of the disease. We also showed that LAVI enlargement might be associated with a higher risk of cardiovascular death and hospital admission for heart failure during follow-up. Additional studies are needed to investigate the outcome implication of LAVI in AS, and to determine whether measurement of LAVI should enter, as in primary mitral regurgitation, into the decisionmaking process for aortic valve replacement.

Sources of funding This research did not receive any specific grant from funding agencies in the public, commercial or not-for-profit sectors.

Disclosure of interest The authors declare that they have no competing interest.

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Please cite this article in press as: Rusinaru D, et al. Determinants of left atrial volume index in patients with aortic stenosis: A multicentre pilot study. Arch Cardiovasc Dis (2017), http://dx.doi.org/10.1016/j.acvd.2016.12.016