Methods

Patients with symptomatic low-gradient severe AS and preserved LVEF who underwent AVR were identified from an ongoing registry and were included in the present analysis ( Figure 1 ).

Patient population. AVAi = aortic valve area index; MPG = mean pressure gradient.

Patients were clinically evaluated, and data were collected on a dedicated departmental cardiology information system (EPD-Vision; Leiden University Medical Center, Leiden, The Netherlands) and analyzed retrospectively. Demographics, clinical symptoms (New York Heart Association [NYHA] functional class), cardiovascular risk factors, medications, and the presence of atrial fibrillation, chronic kidney disease (defined as moderately to severely decreased creatinine clearance <45 ml/min), and chronic obstructive pulmonary disease were collected. The institutional review board approved this retrospective analysis of clinically acquired data and waived the need for written patient informed consent.

All patients underwent complete transthoracic echocardiographic examinations using commercially available ultrasound systems (Vivid 7 and E9; GE Vingmed Ultrasound AS, Horten, Norway) equipped with 3.5-MHz or M5S transducers. Two-dimensional, color, pulsed- and continuous-wave Doppler data were acquired in the parasternal and apical views and were stored digitally and analyzed offline on a dedicated workstation (EchoPAC version 112.0.1; GE Vingmed Ultrasound AS). LV dimensions and wall thickness were measured from the parasternal long-axis view according to current recommendations. LV mass was estimated according to the formula of Devereux et al. Relative wall thickness and the ratio of LV mass to LV end-diastolic volume were calculated as previously described. LV end-diastolic and end-systolic volumes were measured in the apical 4- and 2-chamber views and indexed to body surface area, and the LVEF was derived using Simpson’s biplane method. SVi was estimated by multiplying LV outflow tract area by LV outflow tract velocity-time integral on pulsewave Doppler recordings and then indexed to body surface area. Cardiac output was calculated as the product of stroke volume and heart rate. Stroke work was calculated by the formula (mean arterial pressure + mean peak gradient) × stroke volume × 0.0136 and indexed to LV mass. Peak and mean pressure transaortic gradients were measured in the 3- or 5-chamber apical view according to the simplified Bernoulli equation. Aortic valve area was calculated with the continuity equation and then indexed to body surface area. In addition, energy loss index, valvuloarterial impedance, systemic vascular resistance, and systemic arterial compliance were calculated as previously described.

For further evaluation of LV systolic function, off-line 2-dimensional speckle-tracking longitudinal strain analysis was performed on a workstation with commercially available software (EchoPAC version 112.0.1). From the apical 3-, 4-, and 2-chamber views, global longitudinal strain was measured and averaged. Transmitral pulsewave Doppler was used for assessment of LV diastolic function. Additionally, left atrial volume was evaluated according to the biplane area-length method and then indexed to body surface area. Coexisting valvular dysfunction was assessed on the basis of the European Association of Echocardiography and American Society of Echocardiography recommendations.

On the basis of SVi, patients were divided into 2 categories: low flow was defined as SVi ≤35 ml/m ² and normal flow as SVi >35 ml/m ² . Patients were also categorized as having LV global longitudinal strain ≤−15% or >−15%.

The end point of the study was all-cause mortality. All patients were followed up after AVR. Survival data were collected either from the departmental cardiology information system or the Social Security Death Index and were complete for all subjects included in the study.

Categorical variables are expressed as count (frequency) and continuous variables as mean ± SD. Continuous variables were compared between the 2 groups (survivors vs nonsurvivors) with Student’s t test or the Mann-Whitney U test, as appropriate, and categorical variables with the chi-square test or Fisher’s exact test, as appropriate. The intra- and interobserver reproducibility of LV global longitudinal strain and SVi measurements was assessed by the intraclass correlation coefficient. The cumulative event rates were calculated on the basis of the Kaplan-Meier method, and comparisons between groups were assessed by log-rank test. Cox proportional-hazards ratio regression analyses were performed to investigate univariate and multivariate correlates of all-cause mortality. Hazard ratios and 95% confidence intervals (CIs) were reported. Variables with univariate p values <0.10 were entered in the multivariate analysis. The incremental value of flow and LV global longitudinal strain category over a baseline clinical model was estimated by the significant change in the chi-square statistic of the baseline model. The relative fit of each model was calculated with the −2 log likelihood. Moreover, C-statistics were used for model comparison. Statistical significance was considered for p values <0.05. Statistical analysis was performed with SPSS version 20 (SPSS, Inc., Chicago, Illinois).

Results

The baseline characteristics of 134 patients (mean age 75.5 ± 9.9 years, 50% men) are listed in Table 1 . Surgical AVR was performed in 71 patients (53%) and transcatheter AVR in the remaining 63 (47%). Echocardiographic data are listed in Table 2 . Low flow was identified in 48 patients (36%) and normal flow in 86 (64%), whereas LV global longitudinal strain >−15% was observed in 67 patients (51%) and ≤−15% in 65 (49%). LV global longitudinal strain measurement was feasible in 132 patients (98%). The intraclass correlation coefficients for intra- and interobserver reproducibility were 0.95 (95% CI 0.69 to 0.99) and 0.87 (95% CI 0.50 to 0.97) for LV global longitudinal strain, respectively, and 0.90 (95% CI 0.60 to 0.97) and 0.88 (95% CI 0.55 to 0.97) for SVi, respectively.

During a median follow-up period of 1.8 years (interquartile range 0.5 to 3) after AVR, 26 patients (19.4%) died. There were no patients lost to follow-up. At baseline, patients who died more frequently exhibited associated co-morbidities (atrial fibrillation, chronic kidney disease, chronic obstructive pulmonary disease), previous cardiac surgery, and worse NYHA functional class compared with survivors ( Table 1 ). Aortic valve hemodynamics were comparable between nonsurvivors and survivors. However, nonsurvivors had higher LV global afterload, more concentrically remodeled left ventricles, lower flow, and more impaired LV global longitudinal strain than survivors ( Table 2 ).

When dichotomizing the population on the basis of low flow and normal flow, patients with low flow had higher mortality rates at 1-, 2-, and 3-year follow-up after AVR than those with normal flow (16.7%, 25.0%, and 33.3% vs 2.3%, 3.5%, and 4.6%, respectively, log-rank p <0.001). This difference remained significant after adjusting for age, atrial fibrillation, chronic obstructive pulmonary disease, chronic kidney disease, NYHA functional class, and LV global longitudinal strain; patients with normal flow had significantly better outcomes than low-flow patients ( Figure 2 ). When dividing the population according to the prespecified LV global longitudinal strain cut-off value, patients with more impaired global longitudinal strain (>−15%) had significantly increased mortality at 1, 2, and 3 years after AVR in comparison with patients with more preserved global longitudinal strain (≤−15%) (mortality rate 13.4%, 19.4%, and 22.4% vs 1.5%, 3.1%, and 7.7%, respectively, log-rank p = 0.01). Survival remained significantly higher in the cohort of patients with global longitudinal strain ≤−15% after adjusting for age, atrial fibrillation, chronic obstructive pulmonary disease, chronic kidney disease, NYHA functional class, and SVi ( Figure 3 ). Figure 4 shows the cumulative survival for patients grouped according to global longitudinal strain and flow. Patients with global longitudinal strain >−15% and SVi ≤35 ml/m ² had the worse prognosis. There were 6 patients who died <30 days after AVR (50% underwent transcatheter AVR). All of them (100%) had impaired global longitudinal strain (>−15%), and 5 (83%) had low flow. Perioperative mortality was significantly higher in the group with more impaired global longitudinal strain (>−15%) compared with the group with ≤−15% (log-rank p = 0.015) and in the low-flow compared with the normal-flow (log-rank p = 0.014) group.

Impact of flow on survival of patients with low-gradient severe AS and preserved LVEFs after AVR. After adjusting for age, atrial fibrillation, chronic obstructive pulmonary disease, chronic kidney disease, NYHA functional class, and LV systolic function assessed by global longitudinal strain, patients with normal flow (SVi >35 ml/m ² ) had better outcomes than those with low flow (SVi ≤35 ml/m ² ). HR = hazard ratio.

Impact of LV global longitudinal strain (GLS) on survival of patients with low-gradient severe AS and preserved LVEFs after AVR. After adjusting for age, atrial fibrillation, chronic obstructive pulmonary disease, chronic kidney disease, NYHA functional class, and flow expressed as SVi, patients with better GLS (≤−15%) had better outcomes than those with GLS >−15%. HR = hazard ratio.

Impact of flow and LV global longitudinal strain (GLS) on survival of patients with low-gradient severe AS and preserved LVEFs after AVR. Patients with low flow and more impaired GLS (>−15%) had significantly worse outcomes compared with the other groups.

The univariate Cox regression analysis demonstrated that the presence of atrial fibrillation, chronic obstructive pulmonary disease, chronic kidney disease, previous myocardial infarction, and previous cardiac surgery were associated with increased all-cause mortality risk in this population ( Table 3 ). Among the echocardiographic variables, lower valvuloarterial impedance and LV mass/LV end-diastolic volume ratio were associated with improved survival after AVR. Atrial fibrillation and chronic kidney disease were independently associated with mortality after AVR and were selected to build a baseline clinical model to test the independent association between flow and global longitudinal strain with survival ( Table 3 ). Global longitudinal strain >−15% and each 1% impairment in global longitudinal strain were independently associated with all-cause mortality ( Table 4 ). In addition, SVi ≤35 ml/m ² and each 5 ml/m ² decrease in SVi were independently associated with all-cause mortality ( Table 4 ).

Table 3

Univariate and multivariate Cox regression analysis to identify determinants of all-cause mortality in patients with low gradient, preserved ejection fraction severe aortic stenosis after aortic valve replacement

	Univariate Analysis			Multivariate Analysis
	HR	95% CI	p-value	HR	95% CI	p-value
Clinical Variables
Age (years)	1.04	0.99-1.09	0.08	1.01	0.93-1.09	0.78
Male gender	1.49	0.68-3.29	0.32
Body mass index (Kg/m 2 )	1.01	0.91-1.13	0.81
Transcatheter aortic valve replacement	1.69	0.74-3.89	0.21
Logistic EuroScore (%)	1.03	1.00-1.06	0.03	0.98	0.92-1.06	0.69
Coronary artery disease	0.96	0.40-2.27	0.92
Chronic kidney disease	2.60	1.18-5.74	0.02	3.20	1.10-9.31	0.03
Atrial fibrillation	3.45	1.26-9.40	0.02	4.63	1.22-17.62	0.02
Hypertension	2.28	0.78-6.69	0.13
Diabetes	1.64	0.72-3.71	0.24
Hyperlipidemia	0.63	0.28-1.43	0.23
Previous cardiac surgery	2.37	1.06-5.29	0.04	0.97	0.20-4.71	0.97
Myocardial infarction	2.96	1.16-7.55	0.02	2.57	0.55-12.04	0.23
Stroke	2.08	0.76-5.65	0.15
Chronic obstructive pulmonary disease	2.57	1.15-5.77	0.02	1.45	0.49-4.25	0.50
New York Heart Association, class I	Ref		0.08			0.62
II	3.20	0.96-10.47	0.06	1.75	0.45-6.80	0.42
III	2.72	0.77-9.27	0.10	2.07	0.51-8.33	0.31
IV	5.63	1.49-21.15	0.01	2.82	0.55-14.26	0.21
Echocardiographic Variables
Aortic valve area index (cm 2 /m 2 )	0.06	0.001-5.18	0.21
Mean pressure gradient (mmHg)	0.98	0.93-1.05	0.61
Valvulo-arterial impedance (mmHg/ml/m 2 )	1.26	1.02-1.57	0.03	1.08	0.80-1.49	0.66
Left ventricular mass index (g/m 2 )	1.01	0.99-1.02	0.23
Relative wall thickness (%)	1.02	0.99-1.05	0.12
Left ventricular mass / LVEDV ratio (g/ml)	1.63	1.27-2.10	0.001	1.44	0.95-2.17	0.08
Left ventricular ejection fraction (%)	0.94	0.87-1.00	0.07	0.97	0.89-1.06	0.56
Left atrium volume index (ml/m 2 )	0.99	0.97-1.02	0.71

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