Clinical and Genetic Examinations of Dilated Cardiomyopathy
Condition: Dilated Cardiomyopathy
MeSH terms: Cardiomyopathies; Cardiomyopathy, Dilated
Study type: Observational [Patient Registry]

Summary: 
      This study is a descriptive study to investigate clinical and genetic features of dilated
      cardiomyopathy (DCM) patients and their relatives. 109 probands with DCM have been clinically
      characterized with clinical examinations including ECG and echocardiography, and furthermore
      they have had next generation sequencing (NGS) of 42 known DCM genes, and 34 candidate genes.
      The probands were consequtively included in the study and 59 had undergone heart
      transplantation (HTx) upon inclusion. of these patients underwent heart transplantation. The
      data from NGS is validated by Sanger sequencing. In this study we will examine the relatives
      to the 109 index patients by genetic and clinical cascade screening including advanced
      echocardiography including 3D volume measurements and speckle-tracking (GLS). Genetic
      investigations of relatives will be performed if a disease-associated mutation is identifed
      in the proband. Approximately 480 clinical examinations will be performed this way to be able
      to:

      1a. Investigate the frequency of familial types of DCM

      1b. To investigate the yield of genetic and clinical cascade screening

      2. To describe genotype phenotype correlations

      3. To investigate if there are subtle changes in the heart in genopositive individuals which
      do not meet the conventional diagnostic criteria evaluated by advanced echocardiography.
    

Detailed description: 
      Title:

      Clinical and genetic examinations of dilated cardiomyopathy

      Background:

      Dilated cardiomyopathy (DCM) is a severe disease of the heart muscle characterised by reduced
      pumping function and dilatation of the left ventricle without any obvious cause like
      hypertension, ischemic heart disease or heart valve disease. The patients often complain
      about shortness of breath, oedemas, and fatigability. The first sign of the disease can be a
      severe heart rhythm disorder without any preceding symptoms and DCM is not a rare cause of
      suddenly unexpected death. DCM is a frequent reason for heart transplantation and the
      prognosis is severe though improved over the last decades with the implementation of modern
      heart failure treatment.

      The prevalence of DCM is around 1:2500 in the vestern world and multiple screening studies of
      first generation relatives to DCM patients have shown that in 30-50% of the cases it was
      possible to identify at least one other relative with the same disease. The inheritance is
      often dominant and at this point there has been reported disease associated mutations in over
      40 different genes. The clinical examinations of affected families have shown that the
      expression of the disease varies from very critical symptoms and changes in the heart to
      discrete changes of the heart with no accompanying symptoms. Furthermore the time of debut of
      DCM can vary a lot even within the same family and the disease can manifest itself from early
      childhood to late adulthood.

      Newer investigations indicate that a subgroup of approximately 10-15% of inherited DCM cases
      has a higher incidence of severe heart rhythm disorders and thereby worsened prognosis. In a
      considerable part of these families the disease is caused by a genetic mutation in a specific
      gene that codes for a nuclear membrane protein and that mutation is labelled lamin A/C. The
      recognition of the linkage between the genotype and the clinical presentation of the disease
      (phenotype), has formed the foundation of clinical algorithms and made it possible to improve
      the individualised risk stratification and the choice of treatment.

      Status:

      There is a general consensus to offer clinical screening for heart disease to relatives of
      younger DCM patients to be able to detect the disease before symptoms arise and if necessary
      commence early treatment and thus avoid serious disease complications and improve the
      prognosis. In families where the clinical examinations did not reveal any other relatives
      with signs of the disease, it is unclear if there is any benefit in continued controls of the
      apparently healthy relatives to reveal a possible later debut of the disease. The hope is
      that genetic investigations can assist in clarifying this question. If it is possible to
      identify a disease related genetic mutation in the index patient with DCM, it would be
      possible to offer genetic diagnostics to relatives and hereby identify mutation carriers in
      risk of developing the disease and offer these relatives relevant clinical controls and
      disease monitoring, while relatives without the mutation can be discharged without any
      further investigations.

      Until recently it has not been technically and financially possible to offer routine genetic
      diagnostics due to large number of disease related genes and an unknown number of
      unidentified DCM associated genes at this point. Fortunately there has been a revolutionary
      development in DNA sequencing technology through the last couple of years making it possible
      to examine an almost unlimited amount of genes in large patient cohorts fast and to an
      acceptable expense. The Technology is called "Next Generation Sequencing" (NGS), and it can
      also be used to discover new disease associated genes and do genetic association studies.

      Motivation:

      The main supervisor of the project, professor Jens Mogensen has been participating in an EU
      financed FP7 research project called INHERITANCE (INtegrated HEart Research In TrANslational
      genetics and Cardiomyopathies in Europe) since 2010. The purpose of this project is to
      perform clinical and genetic examinations of DCM patients. The project participants comes
      from 11 internationally recognised European centres lead by Professor Arbustini from Pavia in
      Italy (www.inheriatanceproject.eu). Due to the NGS technology is has been possible to make
      genetic examinations on 800 European DCM patients in 42 known disease associated genes as a
      part of the project. Furthermore 34 candidate genes were included which from a theoretical
      point of view could be new disease associated genes. The Danish cohort has contributed with
      140 well characterised DCM patients from Funen and Jutland.

      The raw NGS data performed by the group of Professor Katus in Heidelberg, Germany is being
      assessed by the bioinformatics at the department of clinical genetics in Vejle and they are
      processing the sequencing data on the Danish patients. The first results have been processes
      and the final results are expected to be available in the summer of 2014.

      The Danish DCM cohort is characterised by containing approximately 50% HTx patients and 50%
      with stable disease. This makes it possible to compare the genetic aetiology between the
      consecutively transplanted patients and the non transplanted patients and hereby get an
      impression of the relationship between prognosis and the occurrence of different mutations in
      certain genes.

      Purpose:

      1.To perform clinical and genetic investigations of DCM patients and their relatives to be
      able to:

      1a. Investigate the frequency of familial types of DCM

      1b. Investigate the yield of genetic and clinical cascade screening

      2. Describe genotype phenotype correlations including possible differences in genotype among
      transplanted patients compared to non-transplanted.

      3. Investigate if there are subtle changes in the heart in genopositive individuals which do
      not meet the conventional diagnostic criteria evaluated by advanced echocardiography.

      Research schedule:

      Clinical examinations of index patients:

      Already 109 DCM probands has been included in the cohort and all data is gathered in a
      database.

      Clinical examinations of relatives to the index patients:

        1. Relatives will get a conventional clinical examination according to guidelines, an ECG
           and echocardiography. If it is indicated a MRI scan or invasive investigations will be
           performed according to clinical guidelines.

        2. Conventional echocardiography: Conventional two dimensional (2D), tissue Doppler and
           Doppler echocardiography will be used to evaluate systolic and diastolic function of the
           left ventricle and the outflow tract conditions of the left ventricle (LVOT). The
           examinations will be performed on a Philips Epiq7 medical ultrasound machine and stored
           digitally for later blinded analysis. The examination will be performed according to
           national guidelines hence recording a parasternal long axis view with zoom of the LVOT,
           then a parasternal short axis view on aortic valve, mitral valve and papillary muscle
           level. From the apex recording a 4 chamber view, apical 2 chamber view and apical long
           axis view. When recording 2D, two consecutive loops are saved. Continuous wave (CW)
           Doppler through the aortic valve and the tricuspid valve, pulsed wave (PW) Doppler
           through the LVOT and of the mitral inflow is also performed. PW tissue Doppler of the
           lateral and medial mitral annulus is performed. When performing Doppler examinations
           sweep velocities at 100 mm/s is used with simultaneous ECG registration. Five
           consecutive heart beats are recorded and saved. Furthermore colour Doppler of the
           aortic-, the mitral- and the tricuspid valve is recorded to estimate the degree of
           regurgitation for every valve. More than a mild mitral regurgitation will be further
           quantified by effective regurgitation orifice (ERO).

      Advanced echocardiography: Zoom of the left ventricle with frame rates of 60-100 fps recorded
      in apical 4 chamber, 2 chamber and apical long axis will be performed and saved for later
      blinded analysis with speckle tracking analysis, evaluation of torsion and twist, and global
      longitudinal strain (GLS). Furthermore a zoomed view of the left atrium in 4 chamber and 2
      chamber views will be saved and 3 dimensional (3D) views of the left ventricle, right
      ventricle and left atrium will be performed.

      Time schedule and milestones for the remaining clinical examinations:

      It is expected that relatives to the DCM patients included will be offered the possibility to
      participate in this study. Experience shows that in average about 4 relatives pr index
      patient will be offered clinical examination, thus roughly 480 clinical examinations is still
      to be performed. The clinical examinations will be performed on the cardiology departments at
      Odense University Hospital (OUH) and Aarhus University Hospital (AUH) in collaboration with
      DMSc Hans Eiskjaer. The examinations are expected to be completed in September 2015. The
      relatives will be informed about the genetic results continuously, and they will be offered
      genetic counselling according to usual guidelines.

      Practical preconditions for the clinical examinations to be performed:

      The necessary medical expertise and the necessary medical equipment have to be available at
      the cardiology departments mentioned above.

      Genetic examinations:

      In those cases where a presumable diseas-associated mutation is identified and several family
      members in the same family has DCM, Sanger sequencing of the relevant family members will be
      undertaken. The results will be used in a coherent evaluation to estimate if there is enough
      evidence to classify the sequence variation as definitely disease related or as a variant of
      unknown importance.

      Time schedule and milestones for the genetic examinations:

      The final NGS sequencing results is expected to be available in the spring of 2014.
      Sequencing of the family members is expected to be performed simultaneously with the clinical
      examinations.

      Practical preconditions for the genetic examinations to be performed:

      The necessary molecular biological expertise and the necessary equipment have to be available
      at the clinical genetic department of Vejle Hospital.

      Supervisors:

      Primary Supervisor: Professor, DMSc, Jens Mogensen, the cardiology department of OUH Co
      supervisor: DMSc Jacob Moeller, the cardiology department of OUH Co supervisor: DMSc Hans
      Eiskjaer, the cardiology department of AUH

      Ethical considerations:

      It is likely that the participants in the study will benefit from the results with regards to
      enhanced individual counselling and risk stratification. If the participants do not wish to
      know of their own or their relatives genetic constitution it will be respected and
      considerations regarding diagnostics and treatment will follow the applicable international
      guidelines. It is the supervisors and the other ones responsible for the project perception
      that the possible benefits, outweighs the risks and side effects of this study. The project
      has been approved by the Committee of Health Research Ethics in central Denmark region and is
      furthermore approved by the Danish Data Protection Agency.
    

Observational model: Family-Based
Time perspective: Prospective
Sampling method: Probability Sample
Study population: 
        Families in Denmark with history of dilated cardiomyopathy. Patients mainly from Funen and
        Jutland.
      
Biospecimen description: 
      DNA for genetic testing