Novel Cardiac Imaging Prognostic Markers of Clinical Outcome in Patients With Chronic Aortic Regurgitation - Echocardiography and Magnetic Resonance

Introduction:

Chronic aortic regurgitation is a common valvular heart disease with prevalence of approximately 1% in European population; affecting rather younger patients. The most common causes of chronic aortic regurgitation in developed countries are calcific aortic valve disease and bicuspid aortic valve. Another relatively frequent cause of the chronic aortic regurgitation is the aortic root dilation, which is genetically determined and it is also frequently diagnosed in younger patients. According to current guidelines for valvular heart disease, surgical treatment is recommended for patients with the severe symptomatic aortic regurgitation and for patients with the severe asymptomatic aortic regurgitation when left ventricular ejection fraction (LV EF) is < 50% or if other cardiothoracic surgery is planned (Class I). Current guidelines also recommend considering surgical strategy (Class IIa) in asymptomatic patients with severe aortic regurgitation, left ventricular ejection fraction (LV EF) ≥ 50% and left ventricular end-systolic diameter > 50 mm or indexed diameter > 25 mm/m2. There are two reasons for considering this earlier surgical treatment. Surgical techniques and perioperative treatment have improved recently and postoperative patient outcome are significantly better. There is also strong evidence that left ventricular (LV) diameter decreases shortly after surgery but left ventricular ejection fraction (LV EF) remains unchanged in majority of patients and left ventricular ejection fraction (LV EF) is one of the main determinants of patient's future quality of life and life expectancy. However, surgical correction might be indicated too late in clinical practice, typically in women. The Mayo Clinic authors group reported that women exhibit an excess late mortality compared to male population. They showed that women were severely symptomatic at the time of surgery compare to male population where left ventricular (LV) enlargement was more frequent. Bonow at al reported 33% incidence of clinical events, death and deterioration of left ventricular ejection fraction (LV EF), in natural history of asymptomatic patients with severe aortic regurgitation and preserved left ventricular ejection fraction (LV EF).

The optimal timing of surgical treatment is crucial but it has not been clearly established yet. New methods of identifying subclinical left ventricular (LV) function impairment are needed for better timing of the surgical strategy. Clinical follow-up with routine echocardiography study is recommended every 6 to12 months in patients with severe asymptomatic aortic regurgitation because sudden deterioration of left ventricular (LV) function might occur and we aim to operate on our patients before this happens. It is clear other parameters are needed than only left ventricular ejection fraction (LV EF) and left ventricular (LV) size. Diffuse myocardial fibrosis is a common feature of pathophysiology of the chronic left ventricular (LV) overload. Left ventricular ejection fraction (LV EF) and left ventricular (LV) size are less sensitive and non-specific markers of this process. Fortunately several novel methods of non-invasive quantification of the diffuse myocardial fibrosis have been introduced recently. The most promising method is the magnetic resonance imaging (MRI) - derived T1 relaxation time mapping introduced by Messroghli in 2004, Modified Look-Locker inversion recovery (MOLLI) sequence. Based on published data, MRI derived native T1 relaxation time is a reliable marker of diffuse myocardial fibrosis. The native T1 relaxation time with cut off value of ≥ 1010 ms is an accurate marker of extensive (>30%) myocardial fibrosis with high sensitivity and specificity (Ss=90%, Sp=73%, area under curve (AUC) =0.82). Extracellular myocardial volume (ECV) calculated from MOLLI sequence is also a sensitive marker of diffuse myocardial fibrosis and extracellular myocardial volume (ECV) cutoff value of ≥ 0.315 showed high accuracy to identify extensive (> 30%) myocardial collagen content (Ss=80%, Sp=90%, AUC =0.85). Speckle tracking echocardiography is another promising imaging method for diffuse myocardial fibrosis. Two-dimensional LV global longitudinal strain (GLS) has a potential to discover subclinical left ventricular (LV) functional impairment

Project Plan:

1. All patients will be scanned by MRI including Modified Look-Locker inversion recovery (MOLLI) within one week after inclusion and all complete and anonymized studies will be sent to CoreLab in IKEM. Off-line analysis will consist of the left and right ventricle volumetric and ejection fraction assessment. The aortic regurgitation will be measured using methods of flow sequence at sinotubular junction level (phantom correction required) and ventricular stroke volume difference. Modified Look-Locker inversion recovery (MOLLI) sequence will be acquired before, 10 and 15 minutes after contrast agent administration. T1 relaxation time will be measured within interventricular septum and ECV will be calculated from T1 relaxation time of the myocardium and the blood pool. Off-line analysis will be performed by two independent operators blinded to clinical and ECHO findings and intra- and inter-observer variability will be calculated.
2. All patients will undergo 2-D and 3-D transthoracic echocardiography within one week after inclusion and every six months during follow-up in each participating centre. All full volume anonymized studies will be sent to the CoreLab in IKEM. Off-line analysis of the left ventricular ejection fraction (LV EF),left ventricular (LV) volume, left ventricular (LV) mass, speckle tracking left ventricular (LV) global longitudinal strain (GLS), radial strain and left ventricular (LV) twist will be performed by two independent operators in a blinded fashion. Similarly aortic regurgitation grade will be assessed by two operators using colour Doppler, vena contracta measurement, and Doppler flow measurements. Inter- and intra-observer variability will be than calculated.
3. In all patients 12-lead electrocardiogram (ECG) will be recorded and blood sample will be taken during each visit. Brain natriuretic peptide serum level will be measured routinely at each participating centre. One blood sample will be stored frozen at -80 C° for further analysis including for example galectin levels, etc. This specific analysis will be performed in 1.Faculty of Medicine Charles University in Prague under the supervision of Prof. Sedmera.
4. Sub-study.