Clinical trial NCT01835054: Determinants of the Progression and Outcome of Mitral Regurgitation
Official title: Determinants of the Progression and Outcome of Mitral Regurgitation-PROGRAM STUDY
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Mitral Valve Insufficiency
Keywords: Mitral regurgitation
Mitral valve prolapse
Echocardiography, Doppler
Stress echocardiography
Cardiopulmonary exercice testing
Magnetic Resonance Imaging
Cardiac neurohormones
Visceral obesity
Cardiometabolic risk
Risk stratification
Lead sponsor: Laval University
Sponsor class: OTHER
Collaborators: name: Canadian Institutes of Health Research (CIHR)
name: Heart and Stroke Foundation of Canada
name: University Hospital, Brest
First posted: 2013-04-18
Enrollment: 440
Sex: ALL
Minimum age (years): 21
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: Cohort will be selected at primary care clinic

Brief summary: 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: 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.

Eligibility criteria: 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)

Primary outcomes:
measure: Combined clinical and echocardiographic endpoint
timeFrame: Patients will be followed for 10 years
Secondary outcomes:
measure: Progression of MR severity
timeFrame: Patients will be followed for 10 years
measure: Progression of pulmonary arterial hypertension
timeFrame: Patients will be folowed for 10 years
measure: Progression of LV dysfuntion prior to surgery
timeFrame: Patients will be followed for 10 years
measure: Maximum exercise capacity at baselin and following mitral valve surgery
timeFrame: Patients will be followed for 10 years
measure: Composite end-point prior to mitral valve surgery
timeFrame: Patients will be followed for 10 years
measure: Composite primary end-point after mitral vale surgery
timeFrame: Patients will be followed for 10 years
measure: Mitral valve surgery
timeFrame: Patients will be followed for 10 years
measure: Arrhythmic burden
timeFrame: Patients will be followed for 10 years
Other outcomes:
Locations:
city: Liège
country: Belgium
facility: University Hospital of Sart Tilman
city: Québec
country: Canada
facility: Institut Universitaire de Cardiologie et de Pneumologie de Québec
city: Brest
country: France
facility: University Hospital (CHU) of Brest, Hôpital La Cavale Blanche
city: Rennes
country: France
facility: University Hospital of Rennes
Study officials:
affiliation: Institut universitaire de cardiologie et de pneumologie de Québec, University Laval
name: Philippe Pibarot, PhD, DVM
role: PRINCIPAL_INVESTIGATOR
References:
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