Determinants of the Progression and Outcome of Mitral Regurgitation

Study Overview
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Brief Summary
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Mitral regurgitation (MR) is one of the most frequent valve lesions, both in North America and in Europe, and its prevalence is increasing with the aging of the population. Organic Mitral Regurgitation (OMR) and Ischemic Mitral Regurgitation are the 2 main categories of MR. Organic or primary MR is caused by an anatomic alteration of the valvular or subvalvular mitral apparatus and refers to rheumatic MR and degenerative MR that includes mitral leaflet prolapse and flail leaflet. In the past 20 years, degenerative MR has become, by far, the most frequent cause of severe MR leading to surgery in the western world. However, the best current treatment for OMR remains uncertain and controversial. We have obtained preliminary data showing that OMR is a dynamic lesion. Hence, the echocardiographic evaluation of MR at rest, as generally performed during routine clinical exam, does not necessarily reflect the status of MR during patient's daily activities and thereby does not adequately assess the risk of rapid progression and poor outcome in these patients. The objective of this study is to identify the independent predictors of disease progression and outcome in patients with asymptomatic chronic OMR and to develop and validate novel imaging and circulating biomarkers to improve risk stratification and therapeutic decision-making process in patients with chronic asymptomatic primary OMR.

Detailed Description
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Mitral regurgitation (MR) is one of the most frequent valve lesions, both in North America and in Europe, and its prevalence is increasing owing to the aging of the population. There are 2 main categories of MR: Organic Mitral Regurgitation (OMR) and Ischemic Mitral Regurgitation. Organic or primary MR is caused by an anatomic alteration of the valvular or subvalvular mitral apparatus and refers to rheumatic MR and degenerative MR that includes mitral leaflet prolapse and flail leaflet. In the past 20 years, degenerative MR has become, by far, the most frequent cause of severe MR leading to surgery in the western world. However, the best current treatment for OMR remains uncertain and controversial. This is, in large part, due to the lack of prospective data on the determinants of OMR progression and outcome. Furthermore, we have obtained preliminary data showing that OMR is a dynamic lesion. Hence, the echocardiographic evaluation of MR at rest, as generally performed during routine clinical exam, does not necessarily reflect the status of MR during patient's daily activities and thereby does not adequately assess the risk of rapid progression and poor outcome in these patients. The general objective of this study is thus: to identify the independent predictors of disease progression and outcome in patients with asymptomatic chronic OMR and to develop and validate novel imaging and circulating biomarkers to improve risk stratification and therapeutic decision-making process in patients with chronic asymptomatic primary OMR. The specific aims of the study are: (1) To obtain and analyze: a) the dynamic changes in MR severity, pulmonary arterial pressure, and LV function during exercise; b) the maximum exercise capacity; c) the metabolic profile; d) the plasma natriuretic peptides, e) the degree and localization of myocardial fibrosis measured by cardiac magnetic resonance Imaging (MRI); f) the blood markers of myocardial extracellular matrix (ECM) turnover; g) the progression of MR severity and LV dysfunction during follow-up; and h) the occurrence of adverse clinical outcomes (i.e. symptoms, LV dysfunction, atrial fibrillation (Holter ECG), pulmonary hypertension, heart failure, cardiovascular death) during follow-up in a series of 440 patients with at least moderate OMR and no symptoms at baseline. (2) To analyze the valve tissue samples explanted from the patients who will undergo mitral valve repair with quadrangular resection during follow-up in order to document the presence of lipids, inflammation, and expression of metalloproteinases (MMPs). (3) To obtain and analyze the postoperative changes in LV geometry and function, pulmonary arterial pressure, symptoms, and exercise capacity in the subset of patients who will undergo mitral valve surgery during follow-up. (4) To evaluate the usefulness of the exercise induced changes in MR severity, pulmonary arterial pressure, and LV function (i.e. contractile reserve), and of the blood levels of natriuretic peptides and ECM biomarkers for the prediction of rapid progression to LV dysfunction and adverse events. (5) To examine the relationship between the metabolic abnormalities linked to visceral obesity and the progression and outcome of OMR. (6) To determine, among the baseline clinical, echocardiographic, MRI, metabolic, and biomarkers variables, those which are independently associated with the progression of MR severity and LV dysfunction, and the occurrence of adverse clinical outcomes in patients with OMR.

Official Title
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Determinants of the Progression and Outcome of Mitral Regurgitation-PROGRAM STUDY

Conditions
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Mitral Valve Insufficiency

Intervention / Treatment
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* Other: Blood biomarkers
* Genetic: DNA collection
* Other: Echocardiography
* Other: Cardiopulmonary exercise testing
* Other: Magnetic resonance imaging (MRI)
* Other: Exercise stress doppler echocardiography
* Other: Holter ECG


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age > 18 or 21 years (Legal age according to the countries involved in this study) Presence of at least mild chronic OMR defined as an ERO ≥10mm2 and/or a regurgitant volume ≥20mL Exclusion Criteria: MR due to ischemic heart disease or cardiomyopathy > mild mitral stenosis, aortic regurgitation, aortic stenosis or pulmonary stenosis previous valve operation history of myocardial infarction or angiographycally documented coronary stenosis congenital or pericardial heart disease endocarditis contra-indication or inability to exercise pregnancy Class I or IIa indication for mitral valve operation according to the 2014 ACC/AHA/ESC guidelines Typical contraindications to contrast-enhanced MRI (surgery in the last 3 months, defibrillator, pericardial electrodes, brain surgery, aneurysm clipping, neurostimulator, electric stimulation device or magnetically activated, cochlear implant, insulin pump or medication delivery device, Swan-Ganz catheter)

Ages Eligible for Study
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Minimum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Patients with mitral regurgitation<br>At study entry, patients have 1) a clinical assessment including metabolic risk profile; 2) a blood sample for analysis of metabolic, cardiac neurohormonal blood biomarkers and DNA collection; 3) a complete rest doppler echocardiography; 4) an exercise stress doppler echocardiography; 5) a cardiopulmonary exercise testing; 6) a magnetic resonance Imaging (MRI); 7) a 24-hour Holter ECG. At follow-up, patients have 1) a clinical events assessment; 2) a blood sample analysis; 3) a resting echocardiography every year; 4) MRI (at preop. evaluation in the subset of patients undergoing surgery); 5) a 24-hour Holter ECG (at 2-year and postop.). | Other: Blood biomarkers<br>* Observational Study using Imaging and Biomarkers<br>Genetic: DNA collection<br>* Observational Study using Imaging and Biomarkers<br>Other: Echocardiography<br>* Observational Study using Imaging and Biomarkers<br>Other: Cardiopulmonary exercise testing<br>* Observational Study using Imaging and Biomarkers<br>Other: Magnetic resonance imaging (MRI)<br>* Observational Study using Imaging and Biomarkers<br>Other: Exercise stress doppler echocardiography<br>* Observational Study using Imaging and Biomarkers<br>Other: Holter ECG<br>* Observational Study using Imaging and Biomarkers<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Combined clinical and echocardiographic endpoint | The primary outcome is the time to occurrence of the first composite end-point: development of symptoms, left ventricular (LV) dysfunction (LV Ejection Fraction<60% and/or LV end diastolic diameter >40mm), ventricular arrhytmia requiring hospitalization, mediaction and/or implantation of defibrillator, atrial fibrillation or flutter, pulmonary arterial hypertension (resting systolic pressure >50mmHg), occurence of pulmonary oedema, congestive heart failure or cardiovascular death. | Patients will be followed for 10 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression of MR severity | The annualized progression rate of MR severity will be calculated as the difference between effective regurgitant orifice, regurgitant volume, and vena contracta width measured at baseline and those measured at the last follow-up divided by the time between the first and last examinations. | Patients will be followed for 10 years | 
| Progression of pulmonary arterial hypertension | The annualized progression rate of resting systolic pulmonary arterial pressure will be calculated. | Patients will be folowed for 10 years | 
| Progression of LV dysfuntion prior to surgery | The annualized progression rate of LVEF, LV end-systolic dimension, and LV myocardial global peak systolic velocities and global longitudinal strain will be calculated. | Patients will be followed for 10 years | 
| Maximum exercise capacity at baselin and following mitral valve surgery | Maximum exercise capacity at baseline as measured by the percentage of age and gender predicted VO2max. We will determine which are, among the clinical and Doppler-echocardiographic variables, the independent determinants of maximum exercise capacity at baseline. The baseline exercise capacity will also be used as an independent variable, i.e. we will determine if it is an independent predictor of the primary end-point and of the other secondary end-points | Patients will be followed for 10 years | 
| Composite end-point prior to mitral valve surgery | i.e. follow-up censored at surgery | Patients will be followed for 10 years | 
| Composite primary end-point after mitral vale surgery | i.e. time zero set at surgery | Patients will be followed for 10 years | 
| Mitral valve surgery | Motivated by the occurrence of symptoms, LV systolic dysfunction, atrial fibrillation, and/or resting pulmonary pressure > 50 mmHg. | Patients will be followed for 10 years | 
| Arrhythmic burden | Number and percentage of ventricular ectopic per 24 h, percent time in atrial fibrillation, or flutter per 24 h. | Patients will be followed for 10 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Magnetic Resonance Imaging, Cardiac neurohormones, Cardiometabolic risk, Risk stratification, Mitral regurgitation, Mitral valve prolapse, Echocardiography, Doppler, Stress echocardiography, Cardiopulmonary exercice testing, Visceral obesity