Short summary

Severe mitral valve regurgitation (MR) increases the risk of atrial fibrillation, heart failure and death. Repair of the valve by surgery is recommended when the disease causes symptoms or the heart exhibits signs of failure. However, timing of surgery may be challenging and when signs of cardiac failure develop the injury may be irreversible. The aim of the present study is to investigate the changes in the central blood circulation during both rest and exercise caused by MR, in patients with and without symptoms, and before and after surgery, in order to obtain a better understanding of the relation between the burden of MR on the circulation, fibrosis of the heart muscle and degree of symptoms.

Further, a epidemiologic sub-study aims to assess the importance of inheritance for development of MR.

Rationale

Clinical substudy:

Degenerative mitral valve disease is the most common cause of organic mitral regurgitation (MR) in the Western World. The disease is characterized by prolapse of one or both of the mitral leaflets during systole but includes a broad spectrum of anatomic lesions from fibroelastic defects with isolated prolapse and commonly associated with rupture of the chordae tendinae to diffuse myxomatous degeneration in Barlows disease. The preferred treatment of severe organic mitral regurgitation is surgical correction of the valve (mitral valve repair). According to the current guidelines mitral valve surgery is indicated in symptomatic patients with severe MR. In the asymptomatic patient mitral valve repair is recommended in case of reduced left ventricular ejection fraction (LVEF), atrial fibrillation or in case of more than moderate pulmonary venous hypertension. Optimally the intervention should be timed so that the treatment is appropriately late in the natural history of valve disease to commensurate with the risk of surgery and appropriately early to avoid irreversibly failure of the LV, irreversible remodeling of pulmonary vascular bed and chronic arrhythmias. The optimal timing of surgery is still controversial in the asymptomatic patients without risk factors. In this group it remains unclear whether a "watchful waiting" strategy with regular clinical and echocardiographic controls is preferable to an early surgical strategy. Although no randomized data exist, observational studies indicate that an early intervention is preferable in highly specialized surgical centers with high volume of mitral valve surgery and dedicated mitral valve surgeons. Several observational studies have identified different risk predictors such as the degree of atrial dilatation, the degree of neurohormonal activation and the increase of pulmonary arterial systolic blood pressure estimated by stress echocardiography as independent risk factors in the asymptomatic patient. These predictors are indirect markers of the hemodynamic consequence of mitral regurgitation. Despite this is there only very sparse knowledge of the hemodynamic response to exercise in the asymptomatic patient compared with the symptomatic patient. Furthermore the importance of anatomical differences in type of prolapse and in the degree of myocardial fibrosis due to long-lasting volume overload is unclear for the development of symptoms.

The overall aim of the present study is to obtain a better understanding of the central hemodynamics at rest and during physical exercise in both symptomatic and asymptomatic patients with organic mitral regurgitation, the relation to neurohormonal activation and myocardial fibrosis, and to identify noninvasive echocardiographic measures suitable for estimation of this.

Epidemiological substudy:z

The underlying cause of organic MR often is unknown, but a familial basis for mitral valve prolapse has been suggested. However, the knowledge of inheritance of degenerative mitral valve disease has mainly been based on small observational studies, and case reports. Even though a genetic basis of mitral valve prolapse in selected patients has been described, the extent of familial clustering of diagnosed and operated mitral valve disease is unknown, and it is unknown whether this has any impact on survival. Twin studies provide a unique opportunity to disentangle the effects of genes and environment in a disease.

The aim of the epidemiological sub-study is to assess concordance rates for patients diagnosed or treated for MR in monozygotic twins and dizygotic twins.  Furthermore, to assess the effect of MR in discordant twins on all-cause mortality, and to assess whether having a co-twin with MR affects survival.

Description of the cohort

The study is a prospectively observationally descriptive single center study. Patients aged over 18 evaluated in the outpatient clinic of the Department of Cardiology at Odense University Hospital with known or newly diagnosed severe organic mitral valve regurgitation and preserved left ventricular ejection fraction will be consecutively screened and can be included in the project if no exclusion criteria are met. Forty suitable patients with asymptomatic MR and 40 patients with symptomatic MR undergoing surgical mitral valve repair will be included in the study.

Data and biological material

Clinical data from echocardiography, Magnetic Resonance Imaging (MRI), maximal oxygen consumption test, lung function test etc. will be obtained.

Biological material (blood samples and biopsies from left atrium og ventricle) will be collected.

Register data from the Danish National Patient Registry, the Danish Civil Registration System, The Danish Twin Registry and the National Medical Birth Registry will be used in the epidemiological sub-study. 

Collaborating researchers and departments

Department of Epidemiology, Biostatistics and Biodemography, Institute of Public Health and The Danish Twin Registry, University of Southern Denmark

Department of Clinical Genetics and Department of Clinical Biochemistry and Pharmacology, Odense University Hospital

• Kaare Christensen, MD, DmSc

Department of Cardio-Thoracic Surgery, Odense University Hospital

• Consultant Akhmadjon Irmukhamedov

Department of Clinical Biochemistry, Odense University Hospital

• Professor Lars Melholt

Mayo Clinic, Rochester, USA

• Professor Barry Borlaug
• Postdoc fellow Mads Andersen

Department of Cardiology, Odense University Hospital

• Consultant Karsten Veien, MD
• Consultant Eva Vad Søndergaard, MD