Skip to main content
NCBI home page
European Heart Journal Cardiovascular Imaging logoLink to European Heart Journal Cardiovascular Imaging
. 2017 Jan 7;18(12):1378–1387. doi: 10.1093/ehjci/jew288

Impact of left ventricular remodelling patterns on outcomes in patients with aortic stenosis

Romain Capoulade 1, Marie-Annick Clavel 1, Florent Le Ven 1, Abdellaziz Dahou 1, Christophe Thébault 1, Lionel Tastet 1, Mylène Shen 1, Marie Arsenault 1, Élisabeth Bédard 1, Jonathan Beaudoin 1, Kim O’Connor 1, Mathieu Bernier 1, Jean G Dumesnil 1, Philippe Pibarot 1,*
PMCID: PMC5837780  PMID: 28064154

Abstract

Aims

The objective of this study was to examine the association between the different patterns of left ventricular (LV) remodelling/hypertrophy on all-cause and cardiovascular mortality in patients with aortic stenosis (AS).

Methods and results

In total, 747 consecutive patients (69 ± 14 years, 57% men) with AS and preserved LV ejection fraction were included in this study. According to LV mass index and relative wall thickness, patients were classified into four LV patterns: normal, concentric remodelling (CR), concentric hypertrophy (CH), and eccentric hypertrophy (EH). One hundred and sixteen patients (15%) had normal pattern, 66 (9%) had EH, 169 (23%) had CR, and 396 (53%) had CH. During a median follow-up of 6.4 years, 339 patients died (242 from cardiovascular causes). CH was associated with higher risk of all-cause mortality compared with the three other LV patterns (all P < 0.05). After multivariable adjustment, CH remained associated with higher risk of mortality (HR = 1.27, 95% CI 1.01–1.61, P = 0.046). There was a significant interaction (P < 0.05) between sex and CH with regards to the impact on mortality: CH was associated with worse outcome in women (P = 0.0001) but not in men (P = 0.22). In multivariable analysis, CH remained associated with higher risk of worse outcome in women (HR = 1.56, 95% CI 1.08–2.24, P = 0.018).

Conclusions

This study shows that CH was independently associated with increased risk of mortality in AS patients with preserved ejection fraction. This association was observed in women but not in men. The pattern of LV remodelling/hypertrophy should be integrated in the risk stratification process in patients with AS.

Keywords: aortic stenosis, LV hypertrophy, LV remodelling, mortality, risk stratification

Introduction

Calcific aortic stenosis (AS) is the most common cardiovascular (CV) disease after hypertension and coronary artery disease (CAD) in developed countries.1,2 The pattern of the left ventricular (LV) adaptive response to pressure overload in AS is heterogeneous and includes concentric remodelling (CR), concentric hypertrophy (CH), and eccentric hypertrophy (EH).3,4 The pattern and magnitude of LV hypertrophic remodelling is influenced not only by AS severity but also by several other factors including age, sex, genetic factors, metabolic factors and the coexistence of CAD, hypertension, aortic or mitral regurgitation.5–11 Although the development of LV concentric remodelling or hypertrophy is a physiological response to an increased wall stress aiming to maintain LV ejection fraction (LVEF) and cardiac output, this adaptive response may eventually lead to the development of myocardial fibrosis and potentially irreversible myocardial dysfunction.12–14 Previous studies suggest that severe LV hypertrophy (LVH) is associated with increased risk of cardiac events and mortality in AS patients both prior and after aortic valve replacement (AVR).10,11,15–20 However, there are very limited data on the impact of the different LV remodelling patterns on all-cause mortality in the AS population. The objective of this study was to examine the association between the LV remodelling patterns and mortality in patients with AS and preserved LVEF.

Methods

Patient population

We retrospectively analysed the clinical and Doppler echocardiographic data that were prospectively collected in consecutive patients with AS (inclusion criteria: peak aortic jet velocity > 2.0 m/s) who underwent a comprehensive transthoracic echocardiogram (TTE) at the Québec Heart & Lung Institute between 1999 and 2007. Patients were excluded if they presented the following criteria: (i) LVEF < 50%, (ii) ≥moderate aortic regurgitation, (iii) ≥moderate mitral stenosis or regurgitation, (iv) previous valve intervention, or (v) incomplete clinical and/or Doppler echocardiographic data. According to these criteria, a total of 747 patients were included in this analysis. The study was approved by the Ethics Committee of the Quebec Heart and Lung Institute, and written informed consent was waived for this retrospective analysis.

Clinical data

Clinical data included age, sex, height, weight, body surface area (BSA), body mass index (BMI), systolic and diastolic blood pressure. Clinical comorbidities were documented by review of medical charts and included hypertension [patients receiving antihypertensive medications or having known but untreated hypertension (blood pressure ≥ 140/90 mm Hg)], diabetes (patients receiving oral hypoglycaemic or insulin medications, or, in the absence of such medications, having a fasting glucose ≥7 mmol/L), CAD [history of myocardial infarction, significant coronary artery stenosis (i.e. >50%) on coronary angiography, and/or regional wall motion abnormality on echocardiogram], previous myocardial infraction, chronic obstructive pulmonary disease (COPD), and renal failure (estimated glomerular filtration rate < 60 mL/min/1.73 m2).

Doppler echocardiographic data

All patients underwent a comprehensive TTE exam with Sonos 5500 or IE33 (Philips Healthcare), or using Vivid 7 or 9 (GE) and images were stored digitally. All TTE exams were performed and analysed in the same laboratory by the same team of sonographers and cardiologists following the recommendations of American Society of Echocardiography (ASE) and European Association of Echocardiography [EAE; nowadays European Association of Cardiovascular Imaging (EACVI)].21–23 The echocardiographic data were collected prospectively at the time of the echocardiography and entered in a computerized database.

Aortic valve morphology and function

Stroke volume was calculated by multiplying the LV outflow tract area by the flow velocity–time integral and was indexed to BSA (SVi) or to a 2.04 power of height (SVi2.04).9,24–27 The echocardiographic indices of AS severity included peak aortic jet velocity, mean transvalvular pressure gradient, and aortic valve area calculated by the standard continuity equation and indexed to BSA (AVAi) or to a 2.04 power of height (AVAi2.04). The degree of aortic and mitral regurgitation was classified according to the recommendations of the ASE–EAE/EACVI.28,29

LV geometry and function

LV minor axis internal dimension (LVID), posterior wall thickness (PWT), and inter-ventricular septal thickness (IVST) were measured according to the recommendations of the ASE–EAE/EACVI.21,23 LVEF was measured with the use of the biplane Simpson method.

The relative wall thickness (RWT) was calculated [i.e. RWT = (PWT + IVST)/LVID] and, as recommended, RWT >0.42 was used to define CR (Figure 1).23 LV mass was calculated with the corrected formula of the ASE–EAE/EACVI23 as follows: LVM = 0.8*1.04*[(IVST + LVID + PWT)³ − LVID³]+0.6

Figure 1.

Figure 1

Open in a new tab

Definition and prevalence of LV remodelling patterns. This figure shows the definition and prevalence of LV remodelling patterns in the studied AS population.

LVM was further indexed to BSA (LVMi) or to a 2.7 power of height (LVMi2.7), as previously described to adjust for the effect of obesity on BSA.9,25–27,30–32 LVH was defined as LVMi2.7 >49 g/m2.7 in men and >47 g/m2.7 in women (Figure 1).9,25,26,30–32 By taking into account both values of LVMi2.7 and RWT, patients were classified into four different patterns using the following criteria proposed in the ASE–EACVI guidelines (Figure 1):23 (i) normal pattern: absence of LVH and RWT ≤0.42, (ii) EH: presence of LVH and RWT ratio ≤0.42, (iii) CR: absence of LVH and RWT >0.42, and (iv) CH: presence of LVH and RWT >0.42.

Global LV haemodynamic load

As a measure of global LV haemodynamic load, we calculated the valvulo-arterial impedance: Zva = (SBP + ΔPmean)/SVi where SBP is the systolic blood pressure, ΔPmean the mean transvalvular gradient, and SVi is the stroke volume indexed to BSA (Zva) or to a 2.04 power of height (Zva2.04).9,26,27,33

Study end-points

The study end-points were all-cause mortality and CV mortality. The last update of the clinical events was obtained in all patients from Quebec National Institute of Statistics in January 2013.

Statistical analysis

Continuous data were expressed as mean ± standard deviation or median [interquartile range]. The continuous variables were tested for normality of distribution and homogeneity of variances with the Shapiro–Wilk and Levene tests, respectively. LV remodelling patterns were compared with one-way ANOVA followed by a Tukey’s post hoc test when appropriate. Categorical data were expressed as percentage and compared with the χ2 test or Fisher’s exact test when appropriate.

Kaplan–Meier curves and log-rank tests of the time-to-event data were used to assess the effect of LV remodelling patterns on all-cause and CV mortality. The relationships between RWT, LVMi2.7 or CH pattern and outcomes were assessed with the use of univariable and multivariable Cox proportional hazard analyses. The proportional-hazards assumption was checked with the use of Schoenfeld residuals. The clinically relevant variables and those with P-value <0.10 were entered in the multivariable Cox models (i.e. age, sex, BMI, hypertension, diabetes, CAD, COPD, renal failure, AVAi2.04, SVi2.04, and LVEF). The impact of AVR, defined as a time-dependent variable, on all-cause and CV mortality was analysed in multivariable Cox models. A P-value <0.05 was considered statistically significant.

Results

Patient characteristics

The characteristics of the 747 patients included in this study are presented in Table 1. The mean age was 69 ± 14 years and 57% were men. Seventy percent of patients had hypertension, 25% were obese (i.e. BMI ≥ 30 kg/m2), 25% had diabetes, and 52% had history of CAD. Among the 658 patients (88% of the whole cohort) with evaluation of symptomatic status, 73% presented symptoms (NYHA class ≥2 and/or angina). Concerning the echocardiographic data, 29% of patients had a bicuspid aortic valve and 52% had severe AS.

Table 1.

Baseline clinical characteristics of the study population according to LV remodelling patterns

Whole cohort (n=747) Normal pattern (n= 116) 15% Eccentric hypertrophy (n=66) 9% Concentric remodelling (n=169) 23% Concentric hypertrophy (n=396) 53% P-value†
Clinical data
 Age, years 69 ±14 65 ±16 66 ±15 71 ±12* 70 ±13* <0.0001
 Male gender, % 57% 50% 56% 51% 61% 0.08
 Height, cm 166 ±10 165 ±10 164 ±10 166 ±9 164 ±10 NS
 Weight, kg 74 ±15 71 ±15 75 ±14 72 ±16 76 ±15 0.004
 BSA, m2 1.81 ±0.21 1.77 ±0.21 1.82 ±0.20 1.79 ±0.22 1.82 ±0.26 NS
 BMI, kg/m2 28 ±5 26 ±5 28 ±4* 26 ±4 28 ±5*§ <0.0001
 BMI ≥ 30 kg/m2, % 25% 14% 26% 15% 32%* <0.0001
 History of hypertension, % 70% 61% 70% 64% 75% 0.009
 Systolic blood pressure, mm Hg 134 ±22 132 ±22 132 ±19 131 ±21 136 ±23 NS
 Diastolic blood pressure, mm Hg 73 ±11 72 ±11 70 ±10 73 ±11 73 ±11 NS
 Diabetes, % 25% 22% 24% 19% 29% 0.07
 CAD, % 52% 40% 55% 43% 60%*§ 0.0001
 Prior myocardial infarction, % 23% 18% 27% 14% 27% 0.006
 COPD, % 17% 16% 23% 15% 18% NS
 Renal failure, % 14% 6% 12% 11% 18%* 0.003
Doppler-echocardiographic data
 Bicuspid aortic valve, % 29% 34% 47% 27% 23% NS
 LV outflow tract diameter, cm 2.1 ±0.2 2.1 ±0.2 2.2 ±0.2* 2.1 ±0.2 2.1 ±0.2 <0.0001
 Stroke volume index, mL/m2 41 ±8 41 ±8 45 ±9* 38 ±7* 41 ±8§ <0.0001
 Stroke volume index, mL/m2.04 27 ±6 26 ±5 30 ±6* 24 ±5 27 ±6§ <0.0001
 Peak aortic jet velocity, m/s 3.4 ±0.9 3.0 ±0.7 3.3 ±0.8* 3.1 ±0.7 3.6 ±0.9*§ <0.0001
 Mean transvalvular gradient, mm Hg 29 ±17 21 ±11 27 ±15* 24 ±13 34 ±19*§ <0.0001
 Aortic valve area, cm2 1.01 ±0.30 1.10 ±0.25 1.12 ±0.27 1.03 ±0.27 0.96 ±0.32* <0.0001
 Indexed aortic valve area, cm2/m2 0.56 ±0.17 0.63 ±0.16 0.62 ±0.15 0.58 ±0.16 0.53 ±0.18* <0.0001
 Indexed aortic valve area, cm2/m2.04 0.37 ±0.11 0.40 ±0.10 0.41 ±0.10 0.37 ±0.10 0.35 ±0.12* <0.0001
 IVST, mm 12 ±3 9 ±1 12 ±1* 11 ±2* 14 ±3*§ <0.0001
 PWT, mm 11 ±2 9 ±1 10 ±1* 10 ±1* 12 ±2*§ <0.0001
 LVID, mm 47 ±5 48 ±4 53 ±4* 43 ±4* 48 ±5§ <0.0001
 LV end-diastolic volume, mL 105 ±28 110 ±21 139 ±22* 84 ±16* 107 ±28§ <0.0001
 RWT ratio 0.50 ±0.12 0.37 ±0.04 0.38 ±0.03 0.51 ±0.07* 0.56 ±0.11*§ <0.0001
 LV mass index, g/m2 114 ±32 84 ±14 116 ±17* 88 ±12 134 ±29*§ <0.0001
 LV mass index, g/m2.7 54 ±16 38 ±6 55 ±7* 40 ±5 64 ±15*§ <0.0001
 Valvulo-arterial imped., mm Hg/mL.m2 4.1 ±1.0 3.9 ±0.8 3.6 ±0.8 4.1 ±0.9 4.2 ±1.1* <0.0001
 Valvulo-arterial imped., mm Hg/mL.m2.04 6.3 ±1.6 6.1 ±1.3 5.6 ±1.2 6.5 ±1.4 6.4 ±1.8 0.0002
 Aortic regurgitation grade 0.8 ±0.8 0.9 ±0.8 1.1 ±0.8 0.6 ±0.7 0.9 ±0.8§ 0.0001
 Mitral regurgitation grade 0.8 ±0.7 0.9 ±0.7 1.0 ±0.7 0.7 ±0.7 0.9 ±0.8 0.02
 LVEF, % 65 ±8 65 ±7 63 ±8 68 ±7 65 ±8 <0.0001
Open in a new tab

Values are mean ±SD.

The following symbols indicate the significance of the Tukey’s post hoc test:

*

P < 0.05 from ‘Normal pattern’,

P < 0.05 from ‘EH’,

§

P < 0.05 from ‘CR’.

†

P-value of the one-way ANOVA.

BSA, body surface area; BMI, body mass index; CAD, coronary artery disease; COPD, chronic obstructive pulmonary disease; IVST, inter-ventricular septal thickness; PWT, posterior wall thickness; LVID, left ventricular internal diameter; RWT, relative wall thickness; LVEF, left ventricular ejection fraction.

One hundred sixteen patients (15%) had normal pattern, 66 (9%) had EH, 169 (23%) had CR, and 396 (53%) had CH in this cohort of AS patients with preserved LVEF (Figure 1). None of the patients included in this study had obstructive LVH (i.e. defined as LV outflow tract peak gradient >30 mm Hg). The baseline characteristics of patients according to LV remodelling patterns were presented in Table 1. Concentric patterns (i.e. CR and CH), and especially CH, were more prevalent in older (P = 0.009), obese (P < 0.0001), and hypertensive (P = 0.01) patients (Figure 2C, D, and F). There was only a trend for higher prevalence of CH in men compared with women (P = 0.08), as well as in those with diabetes (P = 0.07) (Figure 2B and E). Patients with more severe AS (P < 0.0001; Figure 2G; see Supplementary data online, figure S1, PanelsA–C) and higher global LV afterload (P ≤ 0.001; see Supplementary data online, Figure S1D and E) had higher prevalence of CH.

Figure 2.

Figure 2

Open in a new tab

Distribution of LV remodelling patterns according to clinical and echocardiographic features. This figure shows the prevalence of patients in each LV remodelling pattern (i.e. normal, EH, CR, and CH defined from LVMi2.7 and RWT) according to definition of LVH (i.e. LVMi2.7 vs. LVMi; A), sex (B), tertiles of age (i.e. age ≤ 66 vs. 66 < age ≤ 76 vs. age > 76 years; C), obesity (i.e. BMI<30 vs. BMI≥30 kg/m2; D), diagnosis of diabetes (E) and hypertension (F), and severe AS (G). P-values are from χ2. AS: aortic stenosis; BMI, body mass index; HTN, hypertension; LVM, left ventricular mass.

LV remodelling and outcomes: impact on all-cause and CV mortality

During the median follow-up of 6.4 years [IQR: 2.6–8.7], there were 339 deaths, of which 242 were from CV cause, and 442 patients underwent AVR (including transcatheter AVR in 23 patients) and 112 underwent concomitant coronary artery bypass grafting at the time of AVR. Despite similar length of follow-up in women vs. men (6.4 [2.6–8.7] vs. 6.4 [2.7–8.6] years, P = 0.96), AVR was less often performed during follow-up in women [164 (51%) AVRs (29 with concomitant CABG)] vs. in men [278 (66%) AVRs (83 with concomitant CABG)] (P < 0.001). There was a significant association (P = 0.0005; Figure 3A) between LV remodelling patterns and all-cause mortality: patients with CH pattern presented the worst survival compared with the three other LV patterns (6 year survival rate: CH = 61% vs. normal = 70% or EH = 71% or CR = 70%; all P < 0.05; Figure 3A).

Figure 3.

Figure 3

Open in a new tab

Overall survival as a function of LV remodelling patterns. This figure shows the survival curves for all-cause mortality in the whole cohort (A), women (B) and men (C) for each LV remodelling pattern (i.e. normal, EH, CR, and CH). The symbols indicate the significant differences between groups: *P<0.05 vs. ‘Normal’; P<0.05 vs. ‘EH’; §P<0.05 vs. ‘CR’. The numbers at the bottom of the graph represent the number of patients at risk at each follow-up time; EH, eccentric hypertrophy; CR, concentric remodeling; CH, concentric hypertrophy.

In univariable Cox analysis, RWT, LVMi2.7, and CH pattern were significantly associated with all-cause mortality (RWT per 0.1 increase: HR = 1.27, 95% CI 1.17–1.38, P < 0.001; LVMi2.7 per 10 g/m2.7 increase: HR = 1.13, 95% CI 1.06–1.19, P < 0.001; and CH: HR = 1.56, 95% CI 1.25–1.94, P < 0.001; Table 2). In multivariable Cox analysis adjusted for age, sex, BMI, hypertension, diabetes, CAD, COPD, renal failure, AVAi2.04, SVi2.04 and LVEF, CH pattern (HR = 1.27, 95% CI 1.01–1.61, P = 0.046; Model #1, Table 2) was independently associated with all-cause mortality, whereas there was only a trend for RWT and LVMi2.7 (RWT: HR = 1.08, 95% CI 0.99–1.19, P = 0.091; LVMi2.7: HR = 1.08, 95% CI 0.99–1.16, P = 0.066; Model #1, Table 2). Similarly, there was a significant association (P = 0.0006) between LV remodelling patterns and CV mortality: CH was associated with worse outcome compared with the three other groups (all P < 0.05; see Supplementary data online, Figure S2A). The univariable and multivariable Cox analyses of CV mortality provided comparable results: after adjustment, LVMi2.7 was independently associated with CV mortality (HR = 1.11, 95% CI 1.01–1.22, P = 0.024) and there was a trend for CH pattern (HR = 1.30, 95% CI 0.98–1.73, P = 0.071), whereas RWT did not reach statistical significance (HR = 1.04, 95% CI 0.93–1.19, P = 0.51) (Model #1, see Supplementary data online, Table S1). Further adjustment for AVR as a time-dependent variable also provided consistent results: LVMI2.7 and CH pattern were independently associated with all-cause (HR = 1.08, 95% CI 1.00–1.17, P = 0.05; HR = 1.27, 95% CI 1.00–1.61, P = 0.047, respectively) and CV mortality [HR = 1.12, 95% CI 1.02–1.22, P = 0.017; HR = 1.30, 95% CI 0.98–1.72, P = 0.072 (trend), respectively]. In these models, AVR was associated with a significant reduction of all-cause mortality (HR = 0.67, 95% CI 0.50–0.89, P = 0.006) and CV mortality (HR = 0.61, 95% CI 0.43–0.86, P = 0.005).

Table 2.

LV remodelling parameters as a function of all-cause mortality

Whole cohort (n=747; 339 deaths)
 Women (n=324; 158 deaths)
 Men (n=423; 181 deaths)
Individual
 Multivariable Model #1
 Individual
 Multivariable Model #2
 Individual
 Multivariable Model #3
HR P-value HR P-value HR P-value HR P-value HR P-value HR P-value
(95% CI) (95% CI) (95% CI) (95% CI) (95% CI) (95% CI)
RWT 1.27 <0.001 1.08 0.091 1.29 <0.001 1.12 0.054 1.22 0.006 1.01 0.86
(by 0.1 increase) (1.17–1.38) (0.99–1.19) (1.17–1.43) (1.00–1.27) (1.06–1.42) (0.87–1.19)
LV mass index, g/m2.7 1.13 <0.001 1.08 0.066 1.32 <0.001 1.16 0.019 1.05 0.26 1.03 0.60
(by 10 g/m2.7 increase) (1.06–1.19) (0.99–1.16) (1.20–1.46) (1.02–1.31) (0.97–1.13) (0.92–1.15)
CH 1.56 <0.001 1.27 0.046 2.06 <0.001 1.56 0.018 1.24 0.15 1.09 0.61
(CH. vs. others) (1.25–1.94) (1.01–1.61) (1.49–2.83) (1.08–2.24) (0.92–1.67) (0.79–1.50)
Open in a new tab

CH, concentric hypertrophy; LVMi, left ventricular mass index; HR, hazard ratio; CI, confidence interval; RWT: relative wall thickness. Model #1 is adjusted for age, sex, BMI, hypertension, diabetes, CAD, COPD, renal failure, aortic valve area indexed to height2.04, stroke volume indexed to height2.04, and LVEF. Models #2 and #3 are Model #1 without adjustment for sex. Results in bold indicate statistically significant associations.

There was no significant interaction between the time period of the baseline echocardiography and the LV remodelling patterns with respect to impact on outcomes (all P > 0.70), suggesting that timing of the baseline exam did not have significant effect on the results.

Sex-difference according to the impact of LV remodelling on outcomes

There was a significant interaction between sex and CH pattern with regards to the prediction of all-cause mortality (P = 0.02) and CV mortality (P = 0.03). The baseline characteristics of patients according to sex were presented in Supplementary data online, Table S2. There was a significant association between LV remodelling patterns and all-cause mortality in women (158 deaths; P = 0.0001; Figure 3B), but not in men (181 deaths; P = 0.22; Figure 3C). Women who had CH presented the worst outcomes compared with those without CH, as well as men with and without CH (all P < 0.05; Figure 4). In the subset of women, CH pattern was associated with higher rate of all-cause mortality compared with the other LV patterns (all P < 0.05; Figure 3B). Consistently, in univariable Cox analysis, RWT, LVMi2.7, and CH pattern were significantly associated with all-cause mortality in women (all P < 0.001; Table 2). In this subset of patients, after multivariable adjustment, LVMi2.7 (HR = 1.16, 95% CI 1.02–1.31, P = 0.019) and CH pattern (HR = 1.56, 95% CI 1.08–2.24, P = 0.018) were independently associated with all-cause mortality, and there was a trend for RWT (HR = 1.12, 95% CI 1.00–1.27, P = 0.054) (Model #2, Table 2). In men, even if RWT was significantly associated with all-cause mortality in univariable analysis (P = 0.006), after similar multivariable adjustment, neither RWT, LVMi2.7, nor CH pattern was associated with all-cause mortality (all P ≥ 0.60; Model #3, Table 2).

Figure 4.

Figure 4

Open in a new tab

Overall survival as a function of sex and CH. This figure shows the survival curves for all-cause mortality according to sex and presence of CH. The symbols indicate the significant differences between groups: *P<0.05 vs. ‘Women-nonCH’; P<0.05 vs. ‘Men-nonCH’; §P<0.05 vs. ‘Men-CH’. The numbers at the bottom of the graph represent the number of patients at risk at each follow-up time; CH, concentric hypertrophy.

The analysis of CV mortality provided comparable results (see Supplementary data online, Figure S2B and C and Table S1). After multivariable adjustment, LVMI2.7 (HR = 1.18, 95% CI 1.03–1.35, P = 0.02) and CH pattern (HR = 1.63, 95% CI 1.07–2.49, P = 0.023) were independently associated with CV mortality in women but not in men (all P ≥ 0.35) (Models #2 and #3, see Supplementary data online, Table S1). Further adjustment for AVR as a time-dependent variable in the subset of women provided similar results: LVMI2.7 and CH pattern remained independently associated with all-cause mortality (HR = 1.16, 95% CI 1.03–1.31, P = 0.017; HR = 1.55, 95% CI 1.08–2.24, P = 0.018, respectively) as well as with CV mortality (HR = 1.19, 95% CI 1.03–1.36, P = 0.015; HR = 1.62, 95% CI 1.07–2.47, P = 0.024, respectively).

Additional adjustment for symptoms, as defined by presence of NYHA class ≥2 and/or angina, or CABG at the time of AVR, provided consistent results regarding association between LVMi2.7 or CH pattern and outcomes (all P ≤ 0.05).

Even if a large proportion of patients were overweight [i.e. 500 (67%) patients had BMI ≥25 kg/m2] or obese [i.e. 187 (25%) patients had BMI ≥30 kg/m2], LVMi2.7 was strongly correlated to LV mass indexed to BSA (LVMi: r = 0.92; P < 0.0001). Using LVH defined by LVMi (i.e. LVMi >115 g/m2 in men and >95 g/m2 in women), the results regarding the relationship between LVMi or CH and all-cause or CV mortality were similar to those obtained with LVMi2.7, even if there was a slight difference in the distribution of LV remodelling patterns according to LVH defined by LVMi vs. LVMi2.7 (Figure 1A).

Discussion

The main findings of this study are as follows: (i) in the present cohort of AS patients with preserved LVEF, CH is the most prevalent pattern followed by CR, whereas EH is rare; (ii) older age, obesity, hypertension, more severe AS, and higher Zva are associated with higher prevalence of CH; (iii) CH is independently associated with increased mortality, even after adjustment for the factors mentioned above and for AVR; and (iv) this association was observed in women but not in men.

LV remodelling in AS

The LV pressure overload related to AS and/or systemic hypertension generally leads to an LV concentric physiologic response with increased wall thickness relative to LV cavity, which limits wall stress to allow for maintenance of normal LV systolic function.3,12,13 Although CR is often considered as the earliest phase on the LV concentric adaptive response to LV pressure overload, a substantial proportion of patients with severe AS remain in CR and never develop CH. In this study that included the whole spectrum of AS, more than half (53%) of patients had CH and 23% had CR and among those with severe AS, 60% had CH and 22% CR. In this cohort with preserved LVEF, the prevalence of EH was, as expected, relatively low (9%). The fact that an important proportion of patients with mild-to-moderate AS nonetheless have CH in this study may be explained, at least in part, by the presence of concomitant systemic hypertension that also contributes to increase the LV afterload. However, it is also interesting to note that in the lower tertile of Zva, which includes mostly patients with mild AS and no hypertension (i.e. patients with mildly increased global haemodynamic load), about 45% of them nonetheless had CH. This finding suggests that beyond the LV haemodynamic load imposed by AS and/or hypertension, other factors, including, age, obesity, metabolic syndrome, insulin resistance, and diabetes, may have an important contribution to the development of LV CR/CH in AS patients.6–9,26,27 These findings suggest that the metabolic milieu, per se, may induce LV CR and/or modulate the LV concentric adaptive response to pressure overload. Moreover, other factors not measured in this study, including genetic factors, may also influence the type and magnitude of the LV remodelling adaptive response to pressure overload.6

The impact of LV remodelling patterns on outcomes in AS

In patients with AS, the presence of LVH is known to be associated with worse LV function, faster progression to symptoms, increased risk of cardiac events, as well as a higher operative risk for surgical AVR and worse mid- or long-term outcomes following surgical or transcatheter AVR.6,10,11,15–20 However, until now, no study has evaluated the prognostic value of the different LV remodelling patterns in a large AS population with preserved LVEF.

This is the first study to demonstrate that CH is a powerful independent predictor of mortality even after adjustment for the correlates of LV remodelling patterns and for the performance of AVR during follow-up. These findings suggest that CH may be associated with an outcome penalty despite successful AVR. These findings support the usefulness of LV remodelling assessment to improve risk stratification in AS patients with preserved LVEF. Several underlying factors and mechanisms may explain the association between CH and increased risk of mortality in AS. CH is associated with reorganization and loss of myocardial cells and development of fibrosis, which is a strong predictor of worse outcomes in AS patients.12,14,34–37 CH and to a lesser extent CR may also result in reduction of stroke volume and thus higher prevalence of paradoxical low flow (reduced stroke volume index despite preserved LVEF), which has been shown to be associated with worse outcomes in the AS population both before and after AVR.38–44 Finally, other pathological mechanisms linked to adverse LV remodelling could explain worse outcomes in AS patients with CH: sub-endocardial ischaemia due to the mismatch between oxygen supply and oxygen need of the hypertrophied myocardium, reduced diastolic perfusion time, microvascular dysfunction, low coronary perfusion pressure, and/or genetic factors associated with LVH.6,45–47

Sex-related differences in the impact of LV remodelling on outcomes

A previous study suggests that among individuals with mild or moderate AS, women tend to develop CR or CH more often, whereas men are more prone than women to develop EH.5 Moreover, in patients with severe AS, other studies reported that women present more concentric LV remodelling pattern than men (i.e. higher RWT, lower LV sizes but similar LVM).48–52 In this study that included the whole range of AS severity, there was a trend for more CH and less CR in men compared with women. One of the most striking results of this study was that the impact of CH on prognosis was much more pronounced in women than in men. Indeed, we demonstrated for the first time that CH was independently associated with a ∼60% increased risk of all-cause or CV mortality in women, whereas there was no significant association between CH and mortality in men. Consistent with these results, a recent study, limited to the analysis of post-AVR outcomes, reported that residual LVH after AVR is associated with increased mortality but this association is much stronger in women.53 Other studies found that women are more likely than men to develop LV restrictive physiology pattern and heart failure in pressure overload cardiopathies.6,54 In response to pressure overload, women may develop a more pronounced form of CR and CH with more important reduction in LV cavity size, decrease in LV compliance and impairment of LV filling and pump function, compared with men.48–52 The nature of the LV remodelling/hypertrophy may also be different in women vs. men with potentially more diffuse myocardial fibrosis in women. Some studies reported that, in the AS population, men tend to have more myocardial fibrosis than women but these studies were confounded by the higher prevalence of CAD in men and by the fact that they measured only focal fibrosis.55,56 Oestrogen, as opposed to testosterone, seems to protect against cardiac fibroblast proliferation.57–59 However, the AS population is predominantly composed of patients >50 years old, and so the vast majority of women with AS are menopaused and have therefore lost, at least in part, the potential protective effect of oestrogen. Other factors could explain the sex-related difference in the impact of CH on outcomes in AS including the fact that, for various reasons, women are often referred to AVR at a later stage of disease compared with men.60 Further studies are needed to elucidate the factors responsible for the differential impact of CH on outcomes in women vs. men with AS.

Clinical implications

In the guidelines for the management of valvular heart disease, the LV remodelling/hypertrophy pattern is not mentioned among the parameters that could be considered to support an indication for AVR.61,62 The ESC-EACTS guidelines however mention ‘excessive’ LVH as one of the criteria that could be considered to suggest (as a Class IIb recommendation) an AVR in asymptomatic patients with severe AS.61 The results of this study as well as some recent studies would support the inclusion of CH as a criterion to recommend AVR in women with severe asymptomatic AS. Indeed further adjustment for AVR (defined as a time-dependent variable) did not affect the association between CH and mortality, which provides further support to the concept that CH has an independent long-term impact on prognosis in AS. These findings thus challenge the ‘wait for symptoms or LV systolic dysfunction’ strategy and would rather support an earlier AVR in patients with severe AS having CH, and particularly in women. However, further prospective studies are needed to (i) confirm our new findings, and, in particular, the potential outcome penalty despite successful AVR in AS patients with CH; and (ii) determine whether earlier intervention could provide a survival benefit in this population.

Study limitations

The main limitations of this work are that the study was conducted in a single centre and that data were prospectively collected but retrospectively queried. Hence, this study has the inherent limitation of a retrospective analysis. A prospective and multi-centre study is needed to confirm and further expand these findings, and especially those related to the differential impact of CH in men vs. women. However, to limit the potential bias associated with this analysis, we included a large series of consecutive patients whose exams were performed and analysed by same and experienced sonographers and cardiologists. Moreover, the mortality data were obtained from the Québec National Institute of Statistics improving the follow-up accuracy. The decision to perform an AVR was taken by the referent physician and could be influenced by his perception and interpretation of disease severity or patient’s symptomatic status.

Cardiac magnetic resonance imaging, which is a gold standard method to assess LV remodelling, was not available for this study. However, 2D TTE has a good reproducibility to evaluate LV geometry and it is the method that is currently recommended and largely used in practice to follow AS patients and trigger intervention. The baseline medication, the assessment of the severity of CAD, and the measurements of myocardial strain and fibrosis, as well as biomarkers, were not available in this study.

Conclusion

LV CH is independently associated with increased all-cause and CV mortality in women with AS and preserved LVEF but not in men. The assessment of LV remodelling patterns should be integrated to the risk stratification of AS patients, and women with LV CH should be followed closely. Further studies are needed to determine whether earlier AVR would improve outcomes in these patients.

Supplementary data

Supplementary data are available at European Heart Journal–Cardiovascular Imaging online.

Supplementary Material

Supplementary Data
Click here for additional data file. (707KB, docx)

Acknowledgements

We thank Isabelle Fortin, Jocelyn Beauchemin, Martine Poulin, and Martine Parent for their help in data collection and management.

Conflict of interest: None declared.

Funding

This work was supported by grants # FDN-143225 and MOP-114997 from the Canadian Institutes of Health Research (CIHR), Ottawa, Ontario, Canada and a grant from the Foundation of the Québec Heart and Lung Institute. R.C. was supported by a post-doctoral fellowship grant from CIHR. F.LV. and C.T. were supported by a clinical and research fellowship grant from Fédération Française de Cardiologie. A.D. was supported by a fellowship grant from L’Agence de la santé et des services sociaux de la Capitale Nationale, Québec, Québec, Canada. M.A. is research scholar from Fonds de Recherche en Santé - Québec (FRSQ), Montreal, Québec, Canada. P.P. holds the Canada Research Chair in Valvular Heart Diseases from CIHR, Ottawa, ON, Canada.

References

  • 1. Nkomo VT, Gardin JM, Skelton TN, Gottdiener JS, Scott CG, Enriquez-Sarano M.. Burden of valvular heart diseases: a population-based study. Lancet 2006;368:1005–1011. [DOI] [PubMed] [Google Scholar]
  • 2. Chaliki HP, Brown ML, Sundt TM, Tajik AJ.. Timing of operation in asymptomatic severe aortic stenosis. Expert Rev Cardiovasc Ther 2007;5:1065–1071. [DOI] [PubMed] [Google Scholar]
  • 3. Grossman W, Jones D, McLaurin LP.. Wall stress and patterns of hypertrophy in the human left ventricle. J Clin Invest 1975;56:56–64. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4. Gerdts E. Left ventricular structure in different types of chronic pressure overload. Eur Heart J 2008;10:E23–E30. [Google Scholar]
  • 5. Cramariuc D, Rieck AE, Staal EM, Wachtell K, Eriksen E, Rossebo AB. et al. Factors influencing left ventricular structure and stress-corrected systolic function in men and women with asymptomatic aortic valve stenosis (a SEAS Substudy). Am J Cardiol 2008;101:510–515. [DOI] [PubMed] [Google Scholar]
  • 6. Gjesdal O, Bluemke DA, Lima JA.. Cardiac remodeling at the population level–risk factors, screening, and outcomes. Nat Rev Cardiol 2011;8:673–685. [DOI] [PubMed] [Google Scholar]
  • 7. Lund BP, Gohlke-Barwolf C, Cramariuc D, Rossebo AB, Rieck AE, Gerdts E.. Effect of obesity on left ventricular mass and systolic function in patients with asymptomatic aortic stenosis (a Simvastatin Ezetimibe in Aortic Stenosis [SEAS] substudy). Am J Cardiol 2010;105:1456–1460. [DOI] [PubMed] [Google Scholar]
  • 8. Lindman BR, Arnold SV, Madrazo JA, Zajarias A, Johnson SN, Perez JE. et al. The adverse impact of diabetes mellitus on left ventricular remodeling and function in patients with severe aortic stenosis. Circ Heart Fail 2011;4:286–292. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9. Pagé A, Dumesnil JG, Clavel MA, Chan KL, Teo K, Tam JW. et al. Metabolic syndrome is associated with more pronounced impairment of LV geometry and function in patients with calcific aortic stenosis: a substudy of the ASTRONOMER trial. (Aortic Stenosis Progression Observation Measuring Effects of Rosuvastatin). J Am Coll Cardiol 2010;55:1867–1874. [DOI] [PubMed] [Google Scholar]
  • 10. Cioffi G, Faggiano P, Vizzardi E, Tarantini L, Cramariuc D, Gerdts E. et al. Prognostic value of inappropriately high left ventricular mass in asymptomatic severe aortic stenosis. Heart 2011;97:301–307. [DOI] [PubMed] [Google Scholar]
  • 11. Duncan AI, Lowe BS, Garcia MJ, Xu M, Gillinov AM, Mihaljevic T. et al. Influence of concentric left ventricular remodeling on early mortality after aortic valve replacement. Ann Thorac Surg 2008;85:2030–2039. [DOI] [PubMed] [Google Scholar]
  • 12. Dweck MR, Boon NA, Newby DE.. Calcific aortic stenosis: a disease of the valve and the myocardium. J Am Coll Cardiol 2012;60:1854–1863. [DOI] [PubMed] [Google Scholar]
  • 13. Gaasch WH, Zile MR.. Left ventricular structural remodeling in health and disease: with special emphasis on volume, mass, and geometry. J Am Coll Cardiol 2011;58:1733–1740. [DOI] [PubMed] [Google Scholar]
  • 14. Hein S, Arnon E, Kostin S, Schonburg M, Elsasser A, Polyakova V. et al. Progression from compensated hypertrophy to failure in the pressure-overloaded human heart: structural deterioration and compensatory mechanisms. Circulation 2003;107:984–991. [DOI] [PubMed] [Google Scholar]
  • 15. Lindman BR, Stewart WJ, Pibarot P, Hahn RT, Otto CM, Xu K. et al. Early regression of severe left ventricular hypertrophy after transcatheter aortic valve replacement is associated with decreased hospitalizations. JACC Cardiovasc Interv 2014;7:662–673. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16. Greve AM, Boman K, Gohlke-Baerwolf C, Kesaniemi YA, Nienaber C, Ray S. et al. Clinical implications of electrocardiographic left ventricular strain and hypertrophy in asymptomatic patients with aortic stenosis: the Simvastatin and Ezetimibe in Aortic Stenosis study. Circulation 2012;125:346–353. [DOI] [PubMed] [Google Scholar]
  • 17. Holme I, Pedersen TR, Boman K, Egstrup K, Gerdts E, Kesaniemi YA. et al. A risk score for predicting mortality in patients with asymptomatic mild to moderate aortic stenosis. Heart 2012;98:377–383. [DOI] [PubMed] [Google Scholar]
  • 18. Cramariuc D, Gerdts E, Davidsen ES, Segadal L, Matre K.. Myocardial deformation in aortic valve stenosis - relation to left ventricular geometry. Heart 2010;96:106–112. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19. Rieck AE, Cramariuc D, Boman K, Gohlke-Barwolf C, Staal EM, Lonnebakken MT. et al. Hypertension in aortic stenosis: implications for left ventricular structure and cardiovascular events. Hypertension 2012;60:90–97. [DOI] [PubMed] [Google Scholar]
  • 20. Orsinelli DA, Aurigemma GP, Battista S, Krendel S, Gaasch WH.. Left ventricular hypertrophy and mortality after aortic valve replacement for aortic stenosis. A high risk subgroup identified by preoperative relative wall thickness. J Am Coll Cardiol 1993;22:1679–1683. [DOI] [PubMed] [Google Scholar]
  • 21. Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA. et al. Recommendations for chamber quantification. Eur J Echocardiogr 2006;7:79–108. [DOI] [PubMed] [Google Scholar]
  • 22. Baumgartner H, Hung J, Bermejo J, Chambers JB, Evangelista A, Griffin BP. et al. Echocardiographic assessment of valve stenosis: EAE/ASE recommendations for clinical practice. Eur J Echocardiogr 2009;10:1–25. [DOI] [PubMed] [Google Scholar]
  • 23. Lang RM, Badano LP, Mor-Avi V, Afilalo J, Armstrong A, Ernande L. et al. 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;16:233–70. [DOI] [PubMed] [Google Scholar]
  • 24. de Simone G, Devereux RB, Daniels SR, Mureddu G, Roman MJ, Kimball TR. et al. Stroke volume and cardiac output in normotensive children and adults. Assessment of relations with body size and impact of overweight. Circulation 1997;95:1837–43. [DOI] [PubMed] [Google Scholar]
  • 25. Cramariuc D, Cioffi G, Rieck AE, Devereux RB, Staal EM, Ray S. et al. Low-flow aortic stenosis in asymptomatic patients: valvular arterial impedance and systolic function from the SEAS substudy. JACC Cardiovasc Imaging 2009;2:390–399. [DOI] [PubMed] [Google Scholar]
  • 26. Capoulade R, Clavel MA, Dumesnil JG, Chan KL, Teo KK, Tam JW. et al. Insulin resistance and LVH progression in patients with calcific aortic stenosis: a substudy of the ASTRONOMER trial. JACC Cardiovasc Imaging 2013;6:165–174. [DOI] [PubMed] [Google Scholar]
  • 27. Capoulade R, Larose E, Mathieu P, Clavel MA, Dahou A, Arsenault M. et al. Visceral adiposity and left ventricular mass and function in patients with aortic stenosis: the PROGRESSA study. Can J Cardiol 2014;30:1080–1087. [DOI] [PubMed] [Google Scholar]
  • 28. Zoghbi WA, Enriquez-Sarano M, Foster E, Grayburn PA, Kraft CD, Levine RA. et al. Recommendations for evaluation of the severity of native valvular regurgitation with two-dimensional and Doppler echocardiography. J Am Soc Echocardiogr 2003;16:777–802. [DOI] [PubMed] [Google Scholar]
  • 29. Lancellotti P, Tribouilloy C, Hagendorff A, Moura L, Popescu BA, Agricola E. et al. European Association of Echocardiography recommendations for the assessment of valvular regurgitation. Part 1: aortic and pulmonary regurgitation (native valve disease). Eur J Echocardiogr 2010;11:223–244. [DOI] [PubMed] [Google Scholar]
  • 30. de Simone G, Daniels SR, Devereux RB, Meyer RA, Roman MJ, de Divitiis O. et al. Left ventricular mass and body size in normotensive children and adults: assessment of allometric relations and impact of overweight. J Am Coll Cardiol 1992;20:1251–1260. [DOI] [PubMed] [Google Scholar]
  • 31. de Simone G, Devereux RB, Roman MJ, Alderman MH, Laragh JH.. Relation of obesity and gender to left ventricular hypertrophy in normotensive and hypertensive adults. Hypertension 1994;23:600–606. [DOI] [PubMed] [Google Scholar]
  • 32. de Simone G, Devereux RB, Daniels SR, Koren MJ, Meyer RA, Laragh JH.. Effect of growth on variability of left ventricular mass: assessment of allometric signals in adults and children and their capacity to predict cardiovascular risk. J Am Coll Cardiol 1995;25:1056–1062. [DOI] [PubMed] [Google Scholar]
  • 33. Hachicha Z, Dumesnil JG, Pibarot P.. Usefulness of the valvuloarterial impedance to predict adverse outcome in asymptomatic aortic stenosis. J Am Coll Cardiol 2009;54:1003–1011. [DOI] [PubMed] [Google Scholar]
  • 34. Dweck MR, Joshi S, Murigu T, Alpendurada F, Jabbour A, Melina G. et al. Midwall fibrosis is an independent predictor of mortality in patients with aortic stenosis. J Am Coll Cardiol 2011;58:1271–1279. [DOI] [PubMed] [Google Scholar]
  • 35. Milano AD, Faggian G, Dodonov M, Golia G, Tomezzoli A, Bortolotti U. et al. Prognostic value of myocardial fibrosis in patients with severe aortic valve stenosis. J Thorac Cardiovasc Surg 2012;144:830–837. [DOI] [PubMed] [Google Scholar]
  • 36. Weidemann F, Herrmann S, Stork S, Niemann M, Frantz S, Lange V. et al. Impact of myocardial fibrosis in patients with symptomatic severe aortic stenosis. Circulation 2009;120:577–584. [DOI] [PubMed] [Google Scholar]
  • 37. Debonnaire P, Delgado V, Bax JJ.. Potential role of fibrosis imaging in severe valvular heart disease. Heart 2015;101:397–407. [DOI] [PubMed] [Google Scholar]
  • 38. Pibarot P, Dumesnil JG.. Low-flow, low-gradient aortic stenosis with normal and depressed left ventricular ejection fraction. J Am Coll Cardiol 2012;60:1845–1853. [DOI] [PubMed] [Google Scholar]
  • 39. Hachicha Z, Dumesnil JG, Bogaty P, Pibarot P.. Paradoxical low flow, low gradient severe aortic stenosis despite preserved ejection fraction is associated with higher afterload and reduced survival. Circulation 2007;115:2856–2864. [DOI] [PubMed] [Google Scholar]
  • 40. Lancellotti P, Magne J, Donal E, Davin L, O'Connor K, Rosca M. et al. Clinical outcome in asymptomatic severe aortic stenosis. Insights from the new proposed aortic stenosis grading classification. J Am Coll Cardiol 2012;59:235–243. [DOI] [PubMed] [Google Scholar]
  • 41. Clavel MA, Dumesnil JG, Capoulade R, Mathieu P, Senechal M, Pibarot P.. Outcome of patients with aortic stenosis, small valve area and low-flow, low-gradient despite preserved left ventricular ejection fraction. J Am Coll Cardiol 2012;60:1259–1267. [DOI] [PubMed] [Google Scholar]
  • 42. Mohty D, Magne J, Deltreuil M, Aboyans V, Echahidi N, Cassat C. et al. Outcome and impact of surgery in paradoxical low-flow, low-gradient severe aortic stenosis and preserved left ventricular ejection fraction: a cardiac catheterization study. Circulation 2013;128:S235–S242. [DOI] [PubMed] [Google Scholar]
  • 43. Dayan V, Vignolo G, Magne J, Clavel MA, Mohty D, Pibarot P.. Outcome and impact of aortic valve replacement in patients with preserved LVEF and low-gradient aortic stenosis. J Am Coll Cardiol 2015;66:2594–603. [DOI] [PubMed] [Google Scholar]
  • 44. Clavel MA, Berthelot-Richer M, Le VF, Capoulade R, Dahou A, Dumesnil JG. et al. Impact of classic and paradoxical low flow on survival after aortic valve replacement for severe aortic stenosis. J Am Coll Cardiol 2015;65:645–653. [DOI] [PubMed] [Google Scholar]
  • 45. Opie LH, Commerford PJ, Gersh BJ, Pfeffer MA.. Controversies in ventricular remodelling. Lancet 2006;367:356–367. [DOI] [PubMed] [Google Scholar]
  • 46. Anderson HV, Stokes MJ, Leon M, Abu-Halawa SA, Stuart Y, Kirkeeide RL.. Coronary artery flow velocity is related to lumen area and regional left ventricular mass. Circulation 2000;102:48–54. [DOI] [PubMed] [Google Scholar]
  • 47. Feihl F, Liaudet L, Waeber B.. The macrocirculation and microcirculation of hypertension. Curr Hypertens Rep 2009;11:182–189. [DOI] [PubMed] [Google Scholar]
  • 48. Kostkiewicz M, Tracz W, Olszowska M, Podolec P, Drop D.. Left ventricular geometry and function in patients with aortic stenosis: gender differences. Int J Cardiol 1999;71:57–61. [DOI] [PubMed] [Google Scholar]
  • 49. Carroll JD, Carroll EP, Feldman T, Ward DM, Lang RM, McGaughey D. et al. Sex-associated differences in left ventricular function in aortic stenosis of the elderly. Circulation 1992;86:1099–1107. [DOI] [PubMed] [Google Scholar]
  • 50. Aurigemma GP, Silver KH, McLaughlin M, Mauser J, Gaasch WH.. Impact of chamber geometry and gender on left ventricular systolic function in patients over 60 years of age with aortic stenosis. Am J Cardiol 1994;74:794–798. [DOI] [PubMed] [Google Scholar]
  • 51. Aurigemma GP, Gaasch WH.. Gender differences in older patients with pressure-overload hypertrophy of the left ventricle. Cardiology 1995;86:310–7. [DOI] [PubMed] [Google Scholar]
  • 52. Douglas PS, Otto CM, Mickel MC, Labovitz A, Reid CL, Davis KB.. Gender differences in left ventricle geometry and function in patients undergoing balloon dilatation of the aortic valve for isolated aortic stenosis. NHLBI Balloon Valvuloplasty Registry. Br Heart J 1995;73:548–54. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53. Gavina C, Falcao-Pires I, Pinho P, Manso MC, Goncalves A, Rocha-Goncalves F. et al. Relevance of residual left ventricular hypertrophy after surgery for isolated aortic stenosis. Eur J Cardiothorac Surg 2016;49:952–9. [DOI] [PubMed] [Google Scholar]
  • 54. Douglas PS, Katz SE, Weinberg EO, Chen MH, Bishop SP, Lorell BH.. Hypertrophy remodeling: gender differences in the early response to left ventricular pressure overload. J Am Coll Cardiol 1998;32:1118–1125. [DOI] [PubMed] [Google Scholar]
  • 55. Petrov G, Dworatzek E, Schulze TM, Dandel M, Kararigas G, Mahmoodzadeh S. et al. Maladaptive remodeling is associated with impaired survival in women but not in men after aortic valve replacement. JACC Cardiovasc Imaging 2014;7:1073–1080. [DOI] [PubMed] [Google Scholar]
  • 56. Azevedo CF, Nigri M, Higuchi ML, Pomerantzeff PM, Spina GS, Sampaio RO. et al. 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. [DOI] [PubMed] [Google Scholar]
  • 57. Weinberg EO, Thienelt CD, Katz SE, Bartunek J, Tajima M, Rohrbach S. et al. Gender differences in molecular remodeling in pressure overload hypertrophy. J Am Coll Cardiol 1999;34:264–273. [DOI] [PubMed] [Google Scholar]
  • 58. Petrov G, Regitz-Zagrosek V, Lehmkuhl E, Krabatsch T, Dunkel A, Dandel M. et al. Regression of myocardial hypertrophy after aortic valve replacement: faster in women? Circulation 2010;122:S23–S28. [DOI] [PubMed] [Google Scholar]
  • 59. Nordmeyer J, Eder S, Mahmoodzadeh S, Martus P, Fielitz J, Bass J. et al. Upregulation of myocardial estrogen receptors in human aortic stenosis. Circulation 2004;110:3270–3275. [DOI] [PubMed] [Google Scholar]
  • 60. Edwards FH, Peterson ED, Coombs LP, DeLong ER, Jamieson WR, Shroyer ALW. et al. Prediction of operative mortality after valve replacement surgery. J Am Coll Cardiol 2001;37:885–892. [DOI] [PubMed] [Google Scholar]
  • 61. Vahanian A, Alfieri O, Andreotti F, Antunes MJ, Baron-Esquivias G, Baumgartner H. et al. Guidelines on the management of valvular heart disease (version 2012). Joint task force on the management of valvular heart disease of the European Society of Cardiology (ESC); European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J 2012;33:2451–2496. [DOI] [PubMed] [Google Scholar]
  • 62. Nishimura RA, Otto CM, Bonow RO, Carabello BA, Erwin JP III, Guyton RA. et al. 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 Am Coll Cardiol 2014;63:e57–185. [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplementary Data
Click here for additional data file. (707KB, docx)

Articles from European Heart Journal Cardiovascular Imaging are provided here courtesy of Oxford University Press

RESOURCES