Association of Aortic Distensibility and Left Ventricular Function in Patients With Stenotic Bicuspid Aortic Valve and Preserved Ejection Fraction: A CMR study

To determine the relationship between aortic distensibility and left ventricular (LV) remodeling, myocardial strain and blood biomarkers in patients with stenotic bicuspid aortic valve (BAV) and preserved ejection fraction (EF) by cardiovascular magnetic resonance (CMR). 43 stenotic BAV patients were prospectively selected for 3.0T CMR. Patients were divided into LV remodeling group (LV mass /volume ≥ 1.15, n=21) and non-remodeling group (LV mass/volume < 1.15, n=22). Clinical characteristics, biochemical data including cardiac troponin T(cTNT), N-terminal pro-B type natriuretic peptide (NT-proBNP) and creatine kinase isoenzyme were noted. Distensibility of middle ascending aorta (mid-AA) and proximal descending aorta, LV structural and functional parameters, global and regional myocardial strain were measured. Compared to non-remodeling group, LV remodeling group had signicantly decreased LV global strain (radial: 26.04±8.70 % vs. 32.92±7.81 %, P=0.009; circumferential: -17.20±3.38 % vs. -19.65±2.34 %, P=0.008; longitudinal: -9.13±2.34 % vs. -11.63±1.99 %, P(cid:0)0.001), while radial and circumferential strain were signicantly reduced at the base (radial: 28.52±9.47 % vs. 39.65±10.33 %, P=0.001; circumferential: -14.45±2.97 % vs. -17.22±2.38 %, P=0.002), longitudinal strain was signicantly reduced at all regions (basal: -5.79±3.43 % vs. -8.65±2.42 %, P=0.003; mid: -8.62±2.21 % vs. -11.33±2.58 %, P=0.001; apical : -12.79±2.49 % vs. -15.04±2.20 %, P=0.003). In addition, mid-AA distensibility was independently associated with LV remodeling (β=-0.282, P=0.003), and it was also signicantly correlated with LV global strain (radial: r=0.392, P=0.009; circumferential: r=-0.348, P=0.022; longitudinal: r=-0.333, P=0.029), cTNT (r=-0.333, P=0.029) and NT-proBNP (r= -0.440, P=0.003). In this cohort with stenotic BAV and preserved EF, mid-AA distensibility is found signicantly associated with LV dysfunction, which may be an important factor for predicting adverse cardiovascular events and a potential therapeutic target to prevent heart failure.


Introduction
Bicuspid aortic valve (BAV) is the most common congenital cardiovascular malformation in adult, affecting 0.5-2% of the population. Almost 50% of BAV subjects with severe aortic stenosis (AS) require surgery in their lifespan [1,2]. BAV is characterized by a narrowed valve ori ce and severe valve calci cation, concomitant AS aggravates the degree of left ventricular (LV) out ow tract obstruction, resulting in increased LV afterload. Studies have indicated that stenotic BAV patients exhibited increased LV mass, depressed LV contractility and impaired diastolic function with marked hemodynamic alterations [3,4]. And notably, the impaired LV diastolic function is related to reduced aortic elasticity [5][6][7], supporting the hypothesis that BAV disease is not con ned to valve but also affects aorta and left ventricle.
Aorta is recognized as a conduit for buffering blood pressure, and its abnormal elastic property is a major contributor to increased LV afterload. LV remodeling, the result of myocardial injury or overload, is manifested by alterations in geometry and structure, systolic and diastolic dysfunction and myocardial brosis [8]. LV remodeling has emerged as a key predictor of adverse cardiovascular events in BAV, especially for patients with signi cant valvular dysfunction [9,10]. However, there has been few reports so far documenting the relationship between aortic distensibility and LV remodeling and myocardial strain in patients with stenotic BAV and preserved ejection fraction (EF).
Cardiovascular magnetic resonance (CMR) is considered the gold standard for evaluating the structure and function of aorta and left ventricle owing to its superior temporal and spatial resolution and less operator dependence. Compared to simple measurements of LVEF, feature-tracking allows comprehensive and quantitative measurements of global and regional myocardial strain, which re ects early and subtle changes in subclinical LV dysfunction [11].
Therefore, the purpose of this study is to determine the relationship between aortic distensibility and LV remodeling, myocardial strain and blood biomarkers in stenotic BAV patients with preserved EF by using CMR.

Study population
BAV patients with moderated to severe AS and persevered EF were diagnosed by transthoracic echocardiography at our institution and prospectively recruited for CMR from September 2020 to November 2021. BAV patients were categorized into two groups according to LV remodeling index as follows: LV remodeling group (LV mass /volume ≥ 1.15, n=21) and non-remodeling group (LV mass/volume < 1.15, n=22).
Moderated to severe AS was de ned as peak velocity ≥ 3.0m/s and (or) mean transaortic pressure gradient ≥ 20 mmHg. Exclusion criteria were as follows: LVEF 50%, other valvular dysfunction (including more than mild aortic insu ciency), aortic dissection , coronary artery disease and myocardial infarction, previous cardiac surgery. The present study conformed to the Declaration of Helsinki and was approved by the Ethics Committee of the Zhongshan Hospital Fudan University, Shanghai, China. Informed consent was obtained from all participants.

Echocardiography
All BAV patients underwent transthoracic echocardiography with a commercially available system (iE33, Philips Medical Systems, Bothell WA, USA). Standard 2D and Doppler echocardiographic examinations were performed at rest in the left lateral decubitus position according to ASE recommendations [12]. The diagnosis of BAV and aortic valve morphology was evaluated in the parasternal short-axis views with only two valve cusps clearly identi ed. Valve morphology was classi ed by lea et fusion type, left and right cusp fusion type (LR), right and non-coronary cusp fusion type (RN) and left and non-coronary cusp fusion type (LN) [13]. Continuous-wave Doppler was used to measure the aortic valve peak velocity. Mean transaortic pressure gradient was calculated using the simpli ed Bernoulli equation.
Aortic and CMR Imaging All examinations were performed on 3.0T scanner (Ingenia CX; Philips Healthcare, Best, The Netherlands) with 32-channel body phased-array surface coil. Aortic and LV images were acquired using ECG-gated steady state free precession acquisition with breath hold. The scanning parameters are as follows: TR 2.6-3.1 msec, TE 1.3-1.5 msec, ip angle 45°, slice thickness 8 mm, 2 mm section gap (for short-axis images), FOV 304 mm×304 mm×8 mm, matrix 152×225×1. The number of images was 25-30 per cardiac cycle. In cine short-axis view, 8-10 continuous images were obtained from mitral valve to LV apex. Cine images of two 2-chamber, 3-chamber and 4-chamber views were also acquired. Based on the transverse, coronal and sagittal positions, cine images of the middle ascending aorta (mid-AA) and proximal descending aorta (PDA) were obtained at the level of the pulmonary artery (Fig.1).

LV Analysis
LV structure and function analysis were performed with commercial postprocessing software (cvi42 v5.11, Circle Cardiovascular Imaging, Alberta, Canada). The short axis stack was analyzed automatically contouring the epicardial and endocardial borders from base to apex at end-diastole and end-systole with manually correction when necessary (Fig.2). LVEF, LV end-systolic volume (LVESV), LV end-diastolic volume (LVEDV), LV stroke volume (LVSV), LV mass (LVM) were quanti ed and indexed to the body surface area (LVESVi, LVEDVi, LVSVi and LVMi, respectively) using the Mosteller formula. The trabeculae and papillary muscles were included. LV remodeling index was de ned as LVM/LVEDV. MR cine images (short-axis, 2-chamber, 3-chamber and 4-chamber views) were input to the Tissue Tracking module for myocardial strain analysis according to the 16 AHA segmentation model. The borders of LV endocardium and epicardium were automatically delineated with manually correction when necessary. Global and regional (basal, mid, apical) strain values in radial, circumferential and longitudinal directions were obtained.

Aortic Distensibility Analysis
Maximum and minimum aortic cross-sectional areas and diameter over the cardiac cycle were determined on the postprocessing software (IntelliSpacePortal version 9.0.4; Philips Healthcare, Best, The Netherlands). Aortic distensibility was calculated by the following equation [14]: (Amax-Amin)/ Amin × (systolic-diastolic blood pressure). Amax and Amin are the maximum systolic aortic area and the minimum diastolic area, respectively. The brachial artery systolic and diastolic blood pressure were measured before CMR examination.

Laboratory testing
Venous blood samples were obtained before CMR examinations for all BAV patients. Cardiac troponin T(cTNT), N-terminal pro-B type natriuretic peptide (NT-proBNP), creatine kinase isoenzyme (CK-MB) levels were measured using the Elecsys Electro-chemo luminescent assay (Cobase 411 analyzer, Roche Diagnostics, Mannheim, Germany) in our laboratory department.

Statistical analysis
Analysis was performed with SPSS 20.0 software (Chicago IL, USA). Normality of data distribution was determined using the histogram and Shapiro-Wilk test. Data were reported as mean ± SD or medians (interquartile ranges) for continuous variables and as frequencies (percentages) for categorical variables.
Differences between two groups were assessed by the Student's T test (Gaussian distribution) or Mann-Whitney U-test (non-Gaussian distribution). Differences in percentages were evaluated using the chisquare tests or Fisher's exact tests. Relationship between aortic distensibility and LV global strain, blood biomarkers were assessed by Pearson's correlation coe cient. Data on cTNT and NT-proBNP were skewed and thus logarithmically transformed. Statistical signi cance was de ned as 2-sided p<0.05.
Multivariate linear regression analysis was performed to determine the independent predictor of LV remodeling. Variables were entered in the model if p <0.10 in univariate analyses. To avoid collinearity between peak velocity and mean transaortic pressure gradient, only peak velocity was entered in the multivariate models. Intra-and interobserver reliabilities were evaluated by the intraclass correlation (ICC).

Baseline characteristics
The demographics and biochemical data of all subjects were summarized in Table 1. There were no differences in age, gender, body mass index, systolic blood pressure, diastolic blood pressure, pulse pressure, heart rate, comorbid condition, medication status and valve phenotype in BAV patients.    All continuous data are presented as mean ± standard deviation.
Mid-AA middle ascending aorta, PDA proximal descending aorta.

Univariable and Multivariable Predictors of LV Remodeling
Univariate and multivariate analysis results are shown in Table 4, gender, body mass index, pulse pressure, mean transvalvular pressure gradient, peak velocity and mid-AA distensibility were correlated with LV remodeling, presented as LV mass/volume. On multivariable regression, only body mass index (β = 0.021, P=0.020), peak velocity (β = 0.112, P=0.024) and mid-AA distensibility (β=-0.282, P=0.003) were independently associated with LV remodeling (R 2 =0.769).  Reproducibility Intra-and interobserver variabilities of MRI parameters (aortic distensibility, LVEDVi, LVMi, GRS, GCS, GLS) were obtained with 26 random cases by two observers. The intra-and inter-observer variability results were shown in Table 5. All the MRI parameters demonstrated good agreements.

Discussion
Current ESC/EACTS guideline has formulated strong recommendations for early intervention in patients with symptomatic severe AS or those who are asymptomatic but with impaired LV function (LVEF<50%) [15]. Management of asymptomatic patients with moderate to severe AS and preserved EF is otherwise controversial [16,17]. BAV with moderate to severe AS is more prevalent in young individuals and is associated with ascending aorta dilatation, aneurysm formation and dissection. Moreover, BAV tends to have a higher degree of LV out ow tract obstruction than the tricuspid aortic valve (TAV) with AS, making it di cult to determine the appropriate interventions and their timing. The present study focused exclusively on stenotic BAV patients with preserved EF and for the rst time, identi ed the signi cant association between mid-AA distensibility and LV dysfunction by means of CMR, providing an additional method for assessing early and subtle ventricular dysfunction.
In this study, we utilized CMR strain-based technique to characterize the global and regional strain. We found a reduction of global myocardial strain in BAV patients with LV remolding, which is consistent with prior echocardiography studies [4,9]. We further demonstrated that the difference in strain was prominent in the base of the heart, which has large amount of myocardial bers of the LV. This pattern of systolic dysfunction is similar to that seen in dilated cardiomyopathy[18] and isolated AS [19]. The asymmetric distribution of myocardial brosis may contribute to the heterogeneous contractile injury in patients with LV out ow tract obstruction. It should be noted that, LV remodeling group exhibited signi cantly decreased strain from base to apex longitudinally when compared to non-remodeling group. GLS has emerged as a more sensitive and objective marker to quantify subendocardial contraction. William et al. [9] reported that impaired GLS was independently associated with adverse cardiovascular events during a median follow-up period of 36 months in BAV patients. In 294 patients with severe AS, Ng et al. [20] revealed that impaired GLS was an independent predictor of all-cause mortality. Thus, tissue tracking technique may facilitate early detection of abnormal LV strain in sentinel regions and identify stenotic BAV patients who might bene t from earlier surgical interventions.
Elastic ber degeneration and extracellular matrix disorder are the major pathogenic mechanism for the impairment of aortic elasticity in stenotic BAV patients [21,22]. In the results of our study, ascending aorta was involved earlier and more obviously, largely due to its high elastin to collagen ratio [23]. It was particularly noticeable that mid-AA distensibility was a signi cant predictor of LV remodeling in patients with stenotic BAV and preserved EF. This association was independent of blood pressure and is similar to the ndings reported by Rider et al. in hypertension patients [24]. It is possible that with the decreased aortic elasticity, accelerated re ected pressure wave arrives in late systole, leading to increased LV afterload, subendocardial ischemia, increased oxygen demand and further interstitial brosis [25][26][27]. The present study supports the hypothesis that aortic stiffening increases the risk of poorer cardiovascular events in stenotic BAV patients through adverse LV remodeling. BAV with AS should be diagnosed at an early stage when LV and aortic remodeling are more likely to be reversible. Optimal medical therapy, especially angiotensin-converting enzyme inhibitor and angiotensin receptor blocker, may have favorable effects before the onset of LV dysfunction by modifying aortic stiffness.
This study also demonstrated that increased aortic stiffening was associated with reduced global myocardial strain in stenotic BAV patients with preserved EF, which is similar to the echocardiography ndings in patients with chronic kidney disease[28] and type 2 diabetes [29]. Additionally, the upregulation of cTNT and NT-proBNP after myocardial dysfunction is closely linked to activation of in ammatory cytokines, oxidative stress and myocardial wall stretch [30,31]. The present study showed a signi cant relationship between mid-AA distensibility and cTNT, NT-proBNP, whose prognostic value has been proven in AS patients [32,33], indicating that stenotic BAV patients with reduced aortic elasticity were probably at a more advanced disease stage.

Study Limitations
This was a cross-sectional study with a small sample size, and the cause-effect relationship between aortic and LV remodeling cannot be identi ed. Therefore, further longitudinal researches with larger sample sizes may be needed. In addition, we did not recruit stenotic TAV as controls, since these patients are older and complicated with more cardiovascular risk factors [34] ,which may cause bias into the study.

Conclusions
The detection of abnormal strain in longitudinal or radial and circumferential at base may aid in identifying sub-clinical LV dysfunction. In line with the concept of ventricular vascular coupling, this CMR study further con rms that mid-AA distensibility is independently associated with LV remodeling. Mid-AA distensibility may therefore represent a valuable indicator for optimized risk strati cation, appropriate timing of intervention for stenotic BAV patients with preserved EF. level of right pulmonary artery (dashed line) and measure diameter and cross-sectional area of mid-AA and PDA; Images of mid-AA and PDA acquired during systole (Plane D) and diastole (Plane E). RN: right and non-coronary cusp fusion type; Mid-AA: middle ascending aorta; PDA: proximal descending aorta.

Figure 2
Examples of LV structure and function analysis on the short-axis cine images. The trace of LV endocardial and epicardial contours from base to apex at end-diastole (Plane A) and end-systole (Plane  Examples of measuring LV myocardial strain by Tissue Tracking software. Standard cardiac images of short-axis (Plane A), two-chamber (Plane B), four-chamber (Plane C) and three-chamber views (Plane D); AHA segmentation of radial (Plane E), circumferential (Plane F) and longitudinal (Plane G) strain.