MULTIMODALITY IMAGING ASSESSMENT OF THE ANATOMY OF THE AORTIC VALVE APPARATUS IN TAVI PATIENTS: IMPLICATIONS FOR PROSTHESIS SIZING AND PARAVALVULAR REGURGITATION

Aortic stenosis (AS) has become the most frequent type of valvular heart disease in Europe and North America. As it primarily presents as calcific AS in adults of advanced age (2\u20137% of the population >65 years), its prevalence is expected to increase further in the future with an aging population. Severe AS is associated with debilitating symptoms (shortness of breath, angina, dizziness, or syncope), and reduced survival if left untreated. According to European Society of Cardiology guidelines, aortic valve replacement (AVR) is the definitive therapy for all patients with symptoms and severe AS, or severe AS with left ventricular systolic dysfunction. However, approximately the 30% of patients referred for AVR are denied surgery because of advanced age, left ventricular dysfunction or comorbidities. Over the last few years, transcatheter aortic valve implantation (TAVI) has been demonstrated to be a feasible and effective therapeutic alternative to traditional AVR for high-risk surgical patients. Clinical trials have shown TAVI to have outcomes similar to surgical AVR up to 2 years after the procedure and excellent outcomes have been confirmed by registry data, with overall survival of 76% at 1 year. TAVI is an invasive technique whose success depends on multidisciplinary team approach, where imaging fulfils a definite part. Pre-procedure imaging is vital to assess the severity of AS, identify eligible candidates, plan the interventional approach, and select the appropriate prosthesis according to the anatomical features. Imaging is pivotal during and after the procedure, guiding prosthesis deployment, providing information regarding valve position, identifying immediate complications, and assessing outcomes. Before TAVI, accurate evaluation of the aortic root dimensions and anatomy is essential for the selection of eligible candidates for the procedure and to ensure the appropriately sized valve prosthesis is chosen. The objective of this thesis is to investigate the incremental value of a multimodality imaging approach to the evaluation of the anatomy of the aortic valve apparatus in TAVI candidates. Chapter 1 illustrates the feasibility and accuracy of 3D transthoracic echocardiography (TTE) compared to 2D TTE and multidetector computed tomography (MDCT) for the measurement of aortic annulus dimensions in the preoperatory evaluation of 100 patients candidates to TAVI. 3D TTE evaluation was feasible in the majority of the patients with low intra and inter observer variability. 3D TTE and MDCT measurements did not differ significantly, with excellent agreement in the selection of cases with too small or too large annulus (recognized exclusion criteria for TAVI) while, as expected due to the oval shape of the aortic annulus, the 2D TTE annulus area, geometrically derived from 2D TTE diameter, was considerably lower in comparison both with 3DTTE and MDCT planimetric surface area. A good agreement in the choice of prosthetic size in cases scheduled for the procedure was found between the 3D TTE and MDCT. Subsequently, even though it\u2019s known that MDCT provides precise information about the annulus anatomy and remains the gold standard for the pre-operative assessment of TAVI candidates, 3D TTE may play a role in those patients that can\u2019t be studied by MDCT for several reasons such as impaired renal function, severe breathlessness, and arrhythmias. 3D TTE does not require breath-old and contrast infusion, may be obtained at the bedside, in more critical cases, and also in the presence of arrhythmias. Chapter 2 shows that cardiac magnetic resonace (CMR), due to its multiplanar reformatting capabilities, allows accurate short-axis visualization of the aortic annulus and precise measurement of the virtual ring corresponding to the site of prosthesis deployment with high reproducibility and accuracy as compared to MDCT. Moreover, it can estimate the coronary ostia height and aortic valve leaflet dimensions that is a key step for patient selection and procedural planning in order to prevent coronary obstruction during TAVI. In Chapter 3 122 aortic patients were studied to evaluate the capability of 3D transesophageal echocardiography (TEE) to estimate preoperatively the distance between the aortic annulus and the left main ostium (AoA-LM), its accuracy in comparison with MDCT-derived measurements, the ability of the 3DTEE-derived measurements in predicting the stent landing zone as defined by the overlap of the prosthesis with mitral leaflet. The results demonstrated that 3D TEE may estimates the AoA-LM distance as an alternative technique to MDCT. Moreover, 3D TEE allows an immediate evaluation of the distance between the mitral leaflet and aortic prosthesis after the implantation. This measurement was feasible in most of the cases (90%) and also accurate. In fact the 3D TEE computed prosthesis was similar to the prosthetic nominal value. Pre and post 3D TEE data concerning the valve and prosthesis morphology and simultaneous real time evaluation of the aortic root including the LM coronary ostium give new insights regarding TAVI and its complications. Chapter 4 suggests that intraoperative 2D and 3D TEE may allow the identification of predictors of significant paravalvular aortic regurgitation (PAR) following successful TAVI. In particular, incomplete device expansion due to aortic valve calcifications is believed to be one of the contributing factors to PAR post-TAVI. In fact, heavily calcified native aortic valves may not allow a perfect apposition of the device along the annulus circumference. Our data, collected in 135 TAVI patients, show that the calcifications of the commissure between the right coronary and non-coronary cusp is related to significant post-procedural PAR. Moreover, the measurement of an \u201carea cover index\u201d, defined as the percentage difference between planimetered aortic annulus area and the nominal prosthesis area, should be considered during patient selection for TAVI. As a low \u201carea cover index\u201d predicts the development of significant post-procedural PAR, this index could be utilized as an additional parameter when choosing the prosthetic size in all those patients with borderline 2D TEE annulus size. Probably a certain degree of prosthetic oversizing is needed in order to minimize the development of significant PAR after the procedure. Chapter 5 shows that, in accordance with previous results, the lack of congruence between prosthesis and annulus size is associated with significant PAR. MDCT is a valuable modality for detecting the mismatch between prosthesis area and aortic annulus area and for predicting PAR. In details, a mismatch of 61.5 mm2 between prosthesis size and aortic annulus area measured by MDCT is a predictor of PAR. In conclusion, advanced cardiac imaging modalities (3D echocardiography, MDCT and MRI), besides standard 2D echocardiography and angiography, play a crucial role in the diagnostic process and management of TAVI patients, allowing proper selection and planning, optimizing the procedure and increasing TAVI success. Echocardiography is the cornerstone of pre-procedure evaluation, complemented by MDCT. Both 3D TTE/TEE and MDCT have a higher predictive value for PAR than 2D echo measurements and have been shown to change valve sizing strategy compared with 2D echo. During TAVI, 2D, and particularly 3D, TEE can be used for guidance and, allowing the visualization of the left main ostium and the measurements of its distance from the annulus, increases the procedure safety. In the future, as patients undergoing TAVI might be younger, CMR might gain significance by the absence of radiation issues

Endothelial Dysfunction in Patients with Severe Mitral Regurgitation

Mitral valve prolapse (MVP) is the most common cause of severe mitral regurgitation. It has been reported that MVP patients-candidates for mitral valve repair (MVRep)-showed an alteration in the antioxidant defense systems as well as in the L-arginine metabolic pathway. In this study, we investigate if oxidative stress and endothelial dysfunction are an MVP consequence or driving factors. Forty-five patients undergoing MVRep were evaluated before and 6 months post surgery and compared to 29 controls. Oxidized (GSSG) and reduced (GSH) forms of glutathione, and L-arginine metabolic pathway were analyzed using liquid chromatography-tandem mass spectrometry methods while osteoprotegerin (OPG) through the ELISA kit and circulating endothelial microparticles (EMP) by flow cytometry. Six-month post surgery, in MVP patients, the GSSG/GSH ratio decreased while symmetric and asymmetric dimethylarginines levels remained comparable to the baseline. Conversely, OPG levels significantly increased when compared to their baseline. Finally, pre-MVRep EMP levels were significantly higher in patients than in controls and did not change post surgery. Overall, these results highlight that MVRep completely restores the increased oxidative stress levels, as evidenced in MVP patients. Conversely, no amelioration of endothelial dysfunction was evidenced after surgery. Thus, therapies aimed to restore a proper endothelial function before and after surgical repair could benefit MVP patients

Machine learning prediction models for mitral valve repairability and mitral regurgitation recurrence in patients undergoing surgical mitral valve repair

Background: Mitral valve regurgitation (MR) is the most common valvular heart disease and current variables associated with MR recurrence are still controversial. We aim to develop a machine learning-based prognostic model to predict causes of mitral valve (MV) repair failure and MR recurrence. Methods: 1000 patients who underwent MV repair at our institution between 2008 and 2018 were enrolled. Patients were followed longitudinally for up to three years. Clinical and echocardiographic data were included in the analysis. Endpoints were MV repair surgical failure with consequent MV replacement or moderate/severe MR (>2+) recurrence at one-month and mod-erate/severe MR recurrence after three years. Results: 817 patients (DS1) had an echocardiographic examination at one-month while 295 (DS2) also had one at three years. Data were randomly divided into training (DS1: n = 654; DS2: n = 206) and validation (DS1: n = 164; DS2 n = 89) cohorts. For intra-operative or early MV repair failure assessment, the best area under the curve (AUC) was 0.75 and the complexity of mitral valve prolapse was the main predictor. In predicting moderate/severe recurrent MR at three years, the best AUC was 0.92 and residual MR at six months was the most important predictor. Conclusions: Machine learning algorithms may improve prognosis after MV repair procedure, thus improving indications for correct candidate selection for MV surgical repair

Markers of subclinical atherosclerosis in patients with aortic valve sclerosis : A meta-analysis of literature studies

Objective: Growing evidence suggested an association between aortic valve sclerosis (AVSc) and cardiovascular (CV) events. However, little is known about the association of AVSc with major markers of subclinical atherosclerosis. We performed a meta-analysis of literature studies to address this issue. Approach and Results: Studies on the relationship between AVSc and common carotid artery intima-media thickness (IMT), prevalence of carotid plaques (CPs), flow-mediated dilation (FMD), aortic pulse wave velocity (PWV) and augmentation index (AIx) were systematically searched in electronic databases. Thirteen studies enrolling 1086 AVSc patients and 2124 controls were included. Compared to controls, AVSc patients showed higher IMT (MD: 0.32 mm; 95%CI: 0.07, 0.58; p=0.014), and higher prevalence of CPs (OR: 4.06; 95%CI: 2.38, 6.93; p<0.001). Moreover, lower FMD (MD: -4.48%; 95%CI: -7.23, -1.74; p=0.001) and higher PWV (MD: 0.96%; 95%CI: 0.11, 1.81; p=0.027) were found in AVSc subjects than in controls, with no differences in AIx (MD: 0.76%; 95%CI: -0.97, 2.49; p=0.389). In Meta-regression analyses body mass index and triglycerides levels have an impact on the difference in IMT between cases and controls, while male gender and smoking habit were associated with the difference in the prevalence of CPs between the two groups. Conclusion: AVSc is significantly associated with altered markers of subclinical atherosclerosis, thus supporting the concept that AVSc and atherosclerosis share common etiopathological mechanism and/or risk factors. On this basis, an echocardiogram carried out to assess the state of the aortic valve would be desirable whenever an altered subclinical marker of atherosclerosis is found

Aortic valve sclerosis adds to prediction of short-term mortality in patients with documented coronary atherosclerosis

Aims: Aortic valve sclerosis (AVSc), a non-uniform thickening of leaflets with an unrestricted opening, is characterized by inflammation, lipoprotein deposition, and matrix degradation. In the general population, AVSc predicts long-term cardiovascular mortality (+50%) even after adjustment for vascular risk factors and clinical atherosclerosis. We have hypothesized that AVSc is a risk-multiplier able to predict even short-term mortality. To address this issue, we retrospectively analyzed 90-day mortality of all patients who underwent isolated coronary artery bypass grafting (CABG) at Centro Cardiologico Monzino over a ten-year period (2006\u20132016). Methods: We analyzed 2246 patients and 90-day all-cause mortality was 1.5% (31 deaths). We selected only patients deceased from cardiac causes (n = 29) and compared to alive patients (n = 2215). A cardiologist classified the aortic valve as no-AVSc (n = 1352) or AVSc (n = 892). Cox linear regression and integrated discrimination improvement (IDI) analyses were used to evaluate AVSc in predicting 90-day mortality. Results: AVSc 90-day survival (97.6%) was lower than in no-AVSc (99.4%; p &lt; 0.0001) with a hazard ratio (HR) of 4.0 (95%CI: 1.78, 9.05; p &lt; 0.0001). The HR for AVSc, adjusted for propensity score, was 2.7 (95%CI: 1.17, 6.23; p = 0.02) and IDI statistics confirmed that AVSc significantly adds (p &lt; 0.001) to the identification of high-risk patients than EuroSCORE II alone. Conclusion: Our data supports the hypothesis that a risk stratification strategy based on AVSc, added to ESII, may allow better recognition of patients at high-risk of short-term mortality after isolated surgical myocardial revascularization. Results from this study warrant further confirmation

Evolution from mitral annular dysfunction to severe mitral regurgitation in Barlow's disease

OBJECTIVES: Barlow's disease (BD) is characterized by thick, redundant mitral valve (MV) leaflets, which can lead to prolapse and significant mitral regurgitation (MR). MV annular abnormalities are also commonly observed and increasingly recognized as possible primary pathology, with leaflet thickening being secondary to increased stress on the MV apparatus. To provide more insights into this hypothesis, the evolution of MV abnormalities over time in patients with BD was assessed.METHODS: A total of 64 patients (54 +/- 12 years, 72% male) with BD who underwent MV surgery and had multiple transthoracic echocardiograms (HE) before surgery were included. In total, 186 TTE were analysed (median time interval 4.2, interquartile range 2.2-6.5 years) including specific MV characteristics.RESULTS: At baseline, MV leaflet length, thickness, billowing height and annular diameter were larger in patients with BD compared to 59 healthy subjects. Systolic outward motion (curling) of the annulus was observed in 77% and severe mitral annular disjunction (>= 5 mm) in 38% of patients with BD. Forty (63%) patients had MR grade I-Il and 24 (37%) MR grade III-IV; at baseline, the 2 groups only differed in left atrial volume and in thickness and billowing height of the posterior leaflet, showing comparable MV annular abnormalities and dilatation despite different grades of MR. Over time, MV annulus diameter, leaflet length and billowing height increased significantly along with MR grade.CONCLUSIONS: In patients with BD, MV annulus abnormalities are present at an early stage and precede the development of significant MR, suggesting their substantial role in the pathophysiology of this disease and as an important target for surgical treatment.Cardiolog

Cardiovascular imaging 2010 in the International Journal of Cardiovascular Imaging

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